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[Display omitted] • The effective integration of machine learning and genetic algorithms to optimize peptide modifications offers a promising avenue for peptide design. • It introduces novel techniques for the directly modification of small peptides, particularly in cases where insufficient data is available for traditional approaches. • It strategically positions the introduction of positive charge amino acids via our model instead of a mere cumulative addition of positive charged amino-acids. • Minimal modifications to the peptide structure can exert a profound influence on the inhibitory activity of LPS-binding peptides. Antimicrobial peptides (AMPs) are valuable alternatives to traditional antibiotics, possess a variety of potent biological activities and exhibit immunomodulatory effects that alleviate difficult-to-treat infections. Clarifying the structure-activity relationships of AMPs can direct the synthesis of desirable peptide therapeutics. In this study, the lipopolysaccharide-binding domain (LBD) was identified through machine learning-guided directed evolution, which acts as a functional domain of the anti-lipopolysaccharide factor family of AMPs identified from Marsupenaeus japonicus. LBD A-D was identified as an output of this algorithm, in which the original LBD Mj sequence was the input, and the three-dimensional solution structure of LBD B was determined using nuclear magnetic resonance. Furthermore, our study involved a comprehensive series of experiments, including morphological studies and in vitro and in vivo antibacterial tests. The NMR solution structure showed that LBD B possesses a circular extended structure with a disulfide crosslink at the terminus and two 3 10 -helices and exhibits a broad antimicrobial spectrum. In addition, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that LBD B induced the formation of a cluster of bacteria wrapped in a flexible coating that ruptured and consequently killed the bacteria. Finally, coinjection of LBD B , Vibrio alginolyticus and Staphylococcus aureus in vivo improved the survival of M. japonicus , demonstrating the promising therapeutic role of LBD B for treating infectious disease. The findings of this study pave the way for the rational drug design of activity-enhanced peptide antibiotics. [ABSTRACT FROM AUTHOR]

Purpose: As they are effective and well tolerated, aminopenicillins are still the cornerstone for the treatment of enterococcal infections. Current treatment guidelines for infective endocarditis (IE) recommend combination treatments, which carry a higher risk of adverse effects and are based on limited in vitro and experimental data. The aim of this study was therefore to evaluate the treatments of enterococcal IE in real-life practice. Methods: A total of 4121 episodes of enterococcal bloodstream infections, occurring between 1994 and 2019, were screened for the evidence of IE. Baseline characteristics, risk factors for complicated infections and treatment information were assessed and analyzed using Cox regression analysis. Results: Overall, 80 (3.9%) IE episodes were identified of which 78 were included in the final analysis. Treatment regimens in our cohort comprised aminopenicillin-monotherapy (n = 20), teicoplanin-monotherapy (n = 26), other monotherapies (OMT) (n = 8), as well as combinations of ampicillin plus daptomycin (n = 8), ampicillin plus gentamicin (n = 4) or other combinations (n = 9). Overall mortality at 28-days was low (9 of 75) and increased to (19 of 75) after 6-months. Frequency of moderate to severe valve regurgitation (p = 0.89), or signs of uncontrolled infection (p = 0.5) and vegetation size ≥ 10 mm (p = 0.11) were similar in the treatment groups. None of the treatment groups was associated with increased hazard for IE-related mortality. Conclusions: This retrospective study complements previous evidence, demonstrating that monotherapy regimens may be a suitable and effective option for the treatment of IE and supports the need for a prospective evaluation of aminopenicillin-monotherapy for initial and subsequent therapy in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Dalbavancin is an antibiotic characterized by an extended half-life and efficacy against methicillin-resistant Staphylococci. Currently, there are only narrative reviews summarizing the evidence about the use of dalbavancin for infective endocarditis (IE), many of which are focused primarily on its use as consolidation therapy. For this reason, we conducted a systematic review to describe the clinical efficacy and the safety of dalbavancin in IE treatment. Methods: We searched for available evidence using the MEDLINE (PubMed), Embase, Scopus, Cochrane Library and Web of Science libraries, with no restrictions regarding the publication year. The risk of bias was performed using the Cochrane ROBINS-I tool for the comparative studies and the Newcastle-Ottawa Scale for descriptive studies. Results: Nine studies were included. All of them were observational. Native valve endocarditis was the most common kind of IE found in the studies' populations (128/263, 48.7%), followed by prosthetic valve endocarditis, and cardiovascular implantable electronic device-related endocarditis. Coagulase-negative Staphylococci were the most common pathogens isolated (83/269, 30.1%), followed by S. aureus, Enterococci spp and Streptococci spp. Five out of nine studies documented a clinical failure rate of less than 10%. Dalbavancin showed a favourable safety profile. Dalbavancin appears to be a promising option for the consolidation therapy of IE. However, further studies comparing dalbavancin with standard of care are needed. PROSPERO registration number: CRD42023430032. [ABSTRACT FROM AUTHOR]

The document published in the American Journal of Respiratory Cell & Molecular Biology explores the association between antibiotic resistance and nonpulmonary sepsis mortality in ICU patients. The study utilized tracheal aspirate metagenomics to analyze bacterial communities and antimicrobial resistance genes (ARGs) in mechanically ventilated patients with sepsis. Findings suggest that the abundance of AMRs in the lungs early in sepsis diagnosis is linked to higher ICU mortality rates, emphasizing the importance of understanding bacterial pathogens in sepsis severity and early response strategies. The study acknowledges limitations such as sample size constraints and the need for further research in this area. [Extracted from the article]

Simple Summary: The rise of antibiotic resistance has driven the search for new and alternative strategies to traditional antimicrobial agents. In this context, the combined use of essential oils and natural antimicrobial peptides represents a promising approach. This study aimed to evaluate the inhibitory effects of three essential oils—winter savory, bergamot, and cinnamon—and the insect-derived antimicrobial peptide Cecropin A, both individually and in combination, against two Gram-negative pathogenic bacteria (Salmonella enterica serovar Thyphimurium and Escherichia coli) as a potential weapon to counteract antimicrobial resistance. The obtained results showed a synergistic effect of essential oils and Cecropin A on both bacteria, suggesting the need for further research to explore the efficacy of natural extracts. These substances hold potential for applications not only in the medical field but also in the food and feed industries. In an era dominated by the phenomenon of antibiotic resistance, it is increasingly important to look for alternatives to synthetic antibiotics. In light of these considerations, the synergistic use of essential oils and Antimicrobial Peptides (AMPs) seems a viable strategy. In this study, we assessed the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Fractional Inhibitory Concentration (FIC) of three Essential Oils (EOs): winter savory (Satureja montana), bergamot (Citrus bergamia) and cinnamon (Cinnamomum zeylanicum) and of the insect antimicrobial peptide Cecropin A (CecA), alone and in combination with EOs, against two Gram-negative ATCC bacterial strains: Escherichia coli and Salmonella enterica serovar Typhimurium. The MIC results showed that winter savory EO (SmEO) and cinnamon EO (CzEO) exhibited the strongest antibacterial activity against both bacterial strains, whereas bergamot EO (CbEO) and CecA demonstrated comparatively lower antibacterial efficacy. These results were also confirmed by the MBC values. The FIC Indices (FICI) revealed that the most effective synergies were observed with the combinations SmEO/CzEO and SmEO/CbEO against E. coli, while against S. enterica Typhimurium the best combinations were CbEO/CzEO and SmEO/CzEO. Regarding CecA, although it was not the most efficient agent either individually or in combination, it is noteworthy that, when combined, it exhibited antibacterial activity even at a 1:64 dilution. [ABSTRACT FROM AUTHOR]

Background: Despite their biocompatibility, metal implants are susceptible to infections, leading to implant failure and patient complications. The purpose of this study was to investigate the antibacterial potential of antibiotic-coated titanium and stainless steel implants. Methods: The study was designed as an experimental in vitro study, and it was conducted at the Department of Immunology of the University of Health Sciences, Istanbul/ Turkiye in January and February 2024. Pieces of titanium and stainless steel were coated with gentamicin, teicoplanin, rifampicin and a combination of rifampicin and gentamicin using a dipping method. Antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus was assessed using zone of inhibition (ZOI) measurements. Results: Both titanium and stainless steel implants displayed significant ZOI values for all antibiotic treatments, indicating effective inhibition of bacterial growth. The combination of gentamicin and rifampicin exhibited the largest ZOI for both implants. Conclusions: Antibiotic-coated titanium and stainless steel implants demonstrate promising potential for reducing implant-associated infections. Further research is needed to optimise the coating method, explore combination therapies and evaluate the long-term efficacy of this approach in clinical settings. [ABSTRACT FROM AUTHOR]

[Display omitted] Although antimicrobial peptides (AMPs) are a promising class of new antibiotics, their inherent susceptibility to degradation requires nanocarrier-mediated delivery. While cubosome nanocarriers have been extensively studied for delivery of AMPs, we do not currently understand why cubosome encapsulation improves antimicrobial efficacy for some compounds but not others. This study therefore aims to investigate the link between the mechanism of action and permeation efficiency of the peptides, their encapsulation efficacy, and the antimicrobial activity of these systems. Encapsulation and delivery of Indolicidin, and its ultra-short derivative, Priscilicidin, were investigated using SAXS, cryo-TEM and circular dichroism. Molecular dynamics simulations were used to understand the loading of these peptides within cubosomes. The antimicrobial efficacy was assessed against gram-negative (E. coli) and gram-positive (MRSA) bacteria. A high ionic strength solution was required to facilitate high loading of the cationic AMPs, with bilayer encapsulation driven by tryptophan and Fmoc moieties. Cubosome encapsulation did not improve the antimicrobial efficacy of the AMPs consistent with their high permeation, as explained by a recent 'diffusion to capture model'. This suggests that cubosome encapsulation may not be an effective strategy for all antimicrobial compounds, paving the way for improved selection of nanocarriers for AMPs, and other antimicrobial compounds. [ABSTRACT FROM AUTHOR]

Porcine blood, a significant byproduct of the pork industry, represents a potential source of antimicrobial peptides (AMPs). AMPs offer a promising alternative to chemical antimicrobials, which can be used as natural preservatives in the food industry. AMPs can exhibit both antibacterial and/or antifungal properties, thus improving food safety and addressing the growing concern of antibiotic and antifungal resistance. The objective of this study was to evaluate the antimicrobial activity of potential AMPs previously identified from porcine cruor hydrolysates. To this end, a total of sixteen peptides were chemically synthesized and their antimicrobial activities (antibacterial, anti-mold, and anti-yeast) were evaluated using microtitration and agar well diffusion methods against a wide range of microorganisms. Five new peptide sequences demonstrated antifungal activity, with Pep5 (FQKVVAGVANALAHKYH), an alpha-helix peptide, exhibiting the most promising results. Pep5 demonstrated efficacy against nine of the eleven fungal isolates, exhibiting low minimum inhibitory concentrations (MICs) and a fungicidal effect against key spoilage fungi (Rhodotorula mucilaginosa, Debaryomyces hansenii, Candida guilliermondii, Paecilomyces spp., Eurotium rubrum, Mucor racemosus, Aspergillus versicolor, Penicillium commune, and P. chrysogenum). These findings illustrate the potential of porcine blood hydrolysates as a source of AMPs, particularly antifungal peptides, which are less known and less studied than the antibacterial ones. Among the tested sequences, Pep5 exhibited the most promising characteristics, including broad-spectrum activity, low MICs, and a fungicidal effect. It is, therefore, a promising candidate for further research and for potential applications in the porcine industry and beyond. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a critical global challenge in the 21st century, validating Sir Alexander Fleming's warning about the misuse of antibiotics leading to resistant microbes. With a dwindling arsenal of effective antibiotics, it is imperative to concentrate on alternative antimicrobial strategies. Previous studies have not comprehensively discussed the advantages and limitations of various strategies, including bacteriophage therapy, probiotics, immunotherapies, photodynamic therapy, essential oils, nanoparticles and antimicrobial peptides (AMPs) within a single review. This review addresses that gap by providing an overview of these various non-antibiotic antimicrobial strategies, highlighting their pros and cons, with a particular emphasis on antimicrobial peptides (AMPs). We explore the mechanism of action of AMPs against bacteria, viruses, fungi and parasites. While these peptides hold significant promise, their application in mainstream drug development is hindered by challenges such as low bioavailability and potential toxicity. However, advancements in peptide engineering and chemical modifications offer solutions to enhance their clinical utility. Additionally, this review presents updates on strategies aimed at improving the cost, stability and selective toxicity of AMPs through the development of peptidomimetics. These molecules have demonstrated effective activity against a broad range of pathogens, making them valuable candidates for integration into surface coatings to prevent device-associated infections. Furthermore, we discuss various approaches for attaching and functionalising these peptides on surfaces. Finally, we recommend comprehensive in vivo studies to evaluate the efficacy of AMPs and their mimetics, investigate their synergistic combinations with other molecules and assess their potential as coatings for medical devices. [ABSTRACT FROM AUTHOR]

Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci. [ABSTRACT FROM AUTHOR]

Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity – the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets. Fifteen crystal structures of β-clamp orthologs were solved, most from Gram-negative bacteria, including eight cocrystal structures with griselimycin. The ensemble of structures samples widely diverse β-clamp architectures and reveals unique protein-ligand interactions with varying degrees of complementarity. Although griselimycin clearly co-evolved with Gram-positive β-clamps, binding affinity measurements demonstrate that the high selectivity observed previously extends to the Gram-negative orthologs, with KD values ranging from 7 to 496 nM for the wild-type orthologs considered. The collective results should aid future structure-guided development of peptide antibiotics against β-clamp proteins of a wide variety of bacterial targets. Structural genomics and binding studies show that a cyclic peptide produced by Streptomyces griseus, griselimycin, exhibits high binding selectivity for diverse DNA polymerase binding sites of various infectious Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Background: The emergence of multidrug-resistant bacteria and also biofilm-associated infections is a great health concern due to the failure of available antibiotics. This has alerted scientists to developing alternative antibiotics. Melittin as an antimicrobial peptide has antibacterial synergistic activity in combining with conventional antibiotics against pathogenic bacteria. Accordingly, this study aimed to assess the synergistic effect of melittin in combination with Ciprofloxacin, Rifampicin, and Chloramphenicol against MDR strains of P. aeruginosa. Materials and methods: Fifty strains of P. aeruginosa were isolated from clinical specimens. The antibiotic susceptibility of isolates was evaluated by the disk diffusion method. The MIC and MBC of melittin and melittin-antibiotics combination against isolated strains were examined by microdilution method. The probable synergism between melittin and antibiotics was assayed using the FIC protocol. Time-killing kinetics and anti-biofilm effects of melittin and melittin-antibiotics combination were evaluated using time-kill kinetics and crystal violet staining method, respectively. The toxicity of the melittin-antibiotics combination on the HEK293 cell line was also assessed by the MTT assay method. Results: Out of 50 isolates of P. aeruginosa , 15 strains are considered to be multidrug strains. Among MDR strains of P. aeruginosa , 42.85% were resistant to cefepime and ceftazidime and all urine-originate isolates were resistant to cotrimoxazole. A combination of MIC dose of ciprofloxacin and melittin decreased resistance against ciprofloxacin up to 33%. The ciprofloxacin-melittin combination showed a favorable synergism and anti-biofilm effect and was also 30.3% less toxic than melittin alone at 4 μg/ml against the HEK293 cell line. In contrast to ciprofloxacin, with the melittin-rifampicin and melittin-chloramphenicol combinations, an addition effect occurred, respectively, in 86.66 and 53.33% of MDR strains of P. aeruginosa. Conclusion: Combining melittin's antibacterial and anti-biofilm properties with traditional antibiotics may offer a novel strategy to address antibiotic resistance in P. aeruginosa. The simultaneous administration of melittin and ciprofloxacin in a single dose has shown a marked increase in antibacterial effectiveness while minimizing toxicity to the HEK293 cell line. It is advisable to conduct additional research to explore the combined antibacterial effects of melittin and ciprofloxacin in a wider range of clinical samples, animal models, and clinical trial settings. [ABSTRACT FROM AUTHOR]

Background: Nocardiosis is an opportunistic infection that has a low prevalence rate, its clinical manifestations are atypical and can be easily misdiagnosed as other diseases. The correct diagnosis and treatment are frequently delayed by various factors. In this case report, we present a pediatric patient with Neuromyelitis Optica Spectrum Disorders who developed Nocardia farcinica pneumonia complicated by pneumocystis jiroveci infection. Case presentation: An 8-year-old girl with chest pain and cough was admitted to the hospital. She suffered from Neuromyelitis Optica Spectrum Disorders and had been taking methylprednisolone and tacrolimus orally for 3 years. She was admitted to the hospital for tests and was diagnosed with acute pneumonia. Despite empiric antibiotic treatment, her condition gradually worsened. Respiratory distress developed, and she needed to use a ventilator for breathing. The symptoms she exhibited led us to suspect the presence of a tumor. Etiological tests later confirmed the co-infection of Nocardia farcinica and Pneumocystis jiroveci. After treatment, the child's lung infection eventually resolved. Conclusion: The Nocardia bacteria and Pneumocystis jiroveci are widely distributed in the environment, possess the capability of systemic dissemination, and exhibit significant resistance to specific treatments. Invasive sampling is frequently necessary for confirming their presence. Timely and accurate diagnosis as well as treatment play a crucial role in patient survival. [ABSTRACT FROM AUTHOR]

Background: Otitis externa (OE) is one of the most frequently diagnosed dermatological diseases in dogs, having a multifactorial aetiology. Among the bacterial agents associated with canine OE, Pseudomonas aeruginosa is of special concern owing to its frequent multidrug resistance profile and ability to form biofilms related to the infection's chronicity and recurrence. Objectives: The main objective of this study was to evaluate and compare the antibiofilm activity of two innovative antimicrobials—an otological gel containing a synthetic antimicrobial peptide and Lavandula angustifolia essential oil—with gentamicin (a conventional antibiotic) using biofilm‐producing P. aeruginosa isolates obtained from dogs with OE. Materials and Methods: The biofilm eradication capacity of gentamicin, otological gel and lavender oil was determined against a collection of 12 P. aeruginosa biofilm‐producers among 35 clinical isolates obtained from the ear canals of dogs with OE. Also, the antimicrobial activity of the otological gel against P. aeruginosa biofilms was assessed in an in vitro model of dog cerumen. Results: Lavender oil showed the best effectiveness after 30 min of contact, eradicating 58.3% (seven of 12) of the isolates, and gentamicin showed full eradication (12 of 12) after 24 h. The otological gel acted more slowly than the lavender oil; yet at 24 h, the antibiofilm capacity of both compounds was similar, with no significant difference between them. It also was found that triglycerides from synthetic cerumen earwax had antipseudomonal activity and, when combined with the otological gel, led to the full eradication of P. aeruginosa. Conclusions and Clinical Relevance: The results of this in vitro study indicate that lavender oil and the otological gel may be effective topical treatments for canine OE promoted by P. aeruginosa biofilm‐producers, as alternatives to gentamicin. Background – Otitis externa (OE) is one of the most frequently diagnosed dermatological diseases in dogs, having a multifactorial aetiology. Among the bacterial agents associated with canine OE, Pseudomonas aeruginosa is of special concern owing to its frequent multidrug resistance profile and ability to form biofilms related to the infection's chronicity and recurrence. Objectives – The main objective of this study was to evaluate and compare the antibiofilm activity of two innovative antimicrobials—an otological gel containing a synthetic antimicrobial peptide and Lavandula angustifolia essential oil—with gentamicin (a conventional antibiotic) using biofilm‐producing P. aeruginosa isolates obtained from dogs with OE. Conclusions and Clinical Relevance – The results of this in vitro study indicate that lavender oil and the otological gel may be effective topical treatments for canine OE promoted by P. aeruginosa biofilm‐producers, as alternatives to gentamicin. [ABSTRACT FROM AUTHOR]

The demand for developing novel antimicrobial drugs has increased due to the rapid appearance and global spread of antibiotic resistance. Antimicrobial peptides (AMPs) offer distinct advantages over traditional antibiotics, such as broad-range efficacy, a delayed evolution of resistance, and the capacity to enhance human immunity. AMPs are being developed as potential medicines, and current computational and experimental tools aim to facilitate their preclinical and clinical development. Structural and functional constraints as well as a more stringent regulatory framework have impeded clinical translation of AMPs as possible therapeutic agents. Although around four thousand AMPs have been identified so far, there are some limitations of using these AMPs in clinical trials due to their safety in the host and sometimes limitations in the biosynthesis or chemical synthesis of some AMPs. Overcoming these obstacles may help to open a new era of AMPs to combat superbugs without using synthetic antibiotics. This review describes the classification, mechanisms of action and immune modulation, advantages, difficulties, and opportunities of using AMPs against multidrug-resistant pathogens and highlights the need and priorities for creating targeted development strategies that take into account the most cutting-edge tools currently available. It also describes the barriers to using these AMPs in clinical trials. [ABSTRACT FROM AUTHOR]

Oral diseases, both acute and chronic, of infectious or non-infectious etiology, represent some of the most serious medical problems in dentistry. Data from the literature increasingly indicate that changes in the oral microbiome, and therefore, the overgrowing of pathological microflora, lead to a variety of oral-localized medical conditions such as caries, gingivitis, and periodontitis. In recent years, compelling research has been devoted to the use of natural antimicrobial peptides as therapeutic agents in the possible treatment of oral diseases. This review focuses on the potential of ceragenins (CSAs), which are lipid analogs of natural antimicrobial peptides, as molecules for the development of new methods for the prevention and treatment of oral diseases. Studies to date indicate that ceragenins, with their spectrum of multidirectional biological activities, including antimicrobial, tissue regeneration-stimulating, anti-inflammatory, and immunomodulatory properties, are strong candidates for further development of oral formulations. However, many of the beneficial properties of ceragenins require confirmation in experimental conditions reproducing the oral environment to fully determine their application potential. Their transition to practical use also requires more advanced testing of these molecules in clinical trials, which have only been conducted in limited numbers to date. [ABSTRACT FROM AUTHOR]

Peptaibols are linear or cyclic peptide antibiotics (peptabiotics) characterized by the presence of a non-proteinogenic alpha-aminoisobutyric amino acid produced by filamentous fungi from the Ascomycota phylum. They exhibit a wide range of biological activities against various microbial pathogens, protozoa, viruses, and tumor cells. In this review we described methods for the fungi cultivation, isolation, screening, purification, as well as peptaibol characterization andtheir biological activities. Currently many techniques for each step of their isolation are known, and we will focus on the most commonly used and recently developed chromatographic and spectroscopic methods for their extraction and identification. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are a diverse class of peptides ubiquitously present in nature, showcasing a broad spectrum of antibacterial activity. Due to their distinctive antibacterial mechanisms, they are considered a novel alternative to conventional antibiotics. In recent decades, substantial research has been conducted on AMPs. However, challenges persist in the development and application of these peptides, including difficulties extraction in vivo, high production costs, systemic cytotoxicity, and instability in physiological conditions. Consequently, scientists employ natural AMPs as a model to generate derived peptides with the aim of creating novel peptide drugs that possess enhanced potency and reduced toxicity. The process of experimental peptide design is deep concerned by its time-consuming, labor-intensive, and costly nature. However, with the continuous advancement of computational methods, publicly accessible databases now offer substantial amounts of AMPs data. These databases serve as a valuable resource for the development and construction of novel AMPs. In this paper, the existing AMP databases and database-aided design methods are reviewed with the aim to provide reference for drug development of AMPs. [ABSTRACT FROM AUTHOR]

Staphylococcus aureusis the leading cause of milk-borne disease in animals and humans worldwide, and it is often contaminated by enterotoxigenic and antimicrobial-resistant S. aureusstrains. The current research work was intented to identify the prevalence of S. aureusfrom samples of bovine milk from various dairy farms and local vendors of Kamrup Metro District, Assam, India, by phenotypic and genotypic identification along with antibiotic resistance profiling. The conventional aseptic methods were implemented for S. aureus isolation from milk in Baird Parker Agar, supplemented with egg yolk and potassium tellurite. Further, the isolates confirmation was carried out using the automated VITEK system and amplification of the S. aureus specific nuc gene by PCR. Antibiotic susceptibility profiling for variety of 16 antibiotics was obtained through the conventional disc diffusion method. Eighty-five presumptive isolates with jetblack colonies with a white halo on Baird Parker Agar were selected. Thirty-eight isolates were eventually confirmed as S. aureus by the automated method and the detection of nuc gene. Antibiotic profiling revealed about 60.52% of the isolates to be multidrug resistant and 55.26a ± 0.01 mm resistant against Kanamycin. The statistical analysis data expressed correlation between Penicillin G and Ampicillin with 42.10b ± 0.01 mm and correlation among Tetracycline, Methicillin and Streptomycin with 10.52h ± 0.01 mm, respectively. Resistance against Kanamycin, Trimethoprim, Cloxacillin, and Nalidixic acid is concerning as such a resistant pattern has not been extensively reported in bovine milk samples in India, which could indicate the possible emergence of MDR S. aureus strains in the study area. [ABSTRACT FROM AUTHOR]

Bombyx mori cecropin A (Bmcecropin A) has antibacterial, antiviral, anti‐filamentous fungal and tumour cell inhibition activities and is considered a potential succedaneum for antibiotics. We clarified the antibacterial mechanism and structure–activity relationships and then directed the structure–activity optimization of Bmcecropin A. Firstly, we found Bmcecropin A shows a strong binding force and permeability to cell membranes like a detergent; Bmcecropin A could competitively bind to the cell membrane with the cell membrane‐specific dye DiI, then damaged the membrane for the access of DiI into the cytoplasm and leading to the leakage of electrolyte and proteins. Secondly, we found Bmcopropin A could also bind to and degrade DNA; furthermore, DNA library polymerase chain reaction (PCR) results indicated that Bmcecropin A inhibited DNA replication by non‐specific binding. In addition, we have identified C‐terminus amidation and serine‐lysine‐ glycine (SLG) amino acids of Bmcecropin A played critical roles in the membrane damage and DNA degradation. Based on the above results, we designed a mutant of Bmcecropin A (E9 to H, D17 to K, K33 to A), which showed higher antibacterial activity, thermostability and pH stability than ampicillin but no haemolytic activity. Finally, we speculated that Bmcecropin A damaged the cell membrane through a carpet model and drew the schematic diagram of its antibacterial mechanism, based on the antibacterial mechanism and the three‐dimensional configuration. These findings yield insights into the mechanism of antimicrobial peptide–pathogen interaction and beneficial for the development of new antibiotics. [ABSTRACT FROM AUTHOR]

Background and Aim: The emergence and proliferation of multidrug-resistant bacteria pose a global health crisis. This issue arises from the overuse and misuse of antibiotics, coupled with the pharmaceutical industry's limited development of new drugs, which is constrained by financial disincentives and regulatory hurdles. This study aimed to investigate the combined antibacterial efficacy and safety profile of the combined ultrashort antimicrobial peptides (AMPs) WW-185 and WOW against antibiotic-resistant bacterial strains. Materials and Methods: The WW-185 and WOW peptides were synthesized through solid-phase methods and purified using reverse-phase high-performance liquid chromatography, and their purity was confirmed by mass spectrometry. Antibacterial activity was evaluated using broth dilution and checkerboard assays to assess both individual and combined effects of the peptides against Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus [MRSA]) and Escherichia coli (including extended-spectrum beta-lactamases [ESBL]-producing strains). The synergy between the peptides was quantified using fractional inhibitory concentration indices. Hemolytic activity was also assessed to determine cytotoxicity toward red blood cells. Results: The combination of WW-185 and WOW exerted synergistic effects against both MRSA and ESBL-producing E. coli, with reduced minimal inhibitory concentrations compared with the individual treatments. The peptides exhibited minimal hemolytic activity, indicating low toxicity. Conclusion: The combination of the ultrashort AMPs WW-185 and WOW shows promising synergistic antibacterial effects against resistant bacteria, with potential for further therapeutic development due to their enhanced efficacy and low toxicity. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs), found in both animals and plants, are used to fend off a wide variety of invading pathogens, such as bacteria, fungi, protozoa, viruses, etc. Their widespread distribution and defensive activity towards all different microbes lead to the successful evolution of complex multicellular organisms. In particular, AMPs target bacterial membranes and disrupt the membrane via the formation of transmembrane pores without interacting with any specific receptors. It is known that different antimicrobial peptides use different mechanisms to disrupt the membrane by forming transmembrane pores. The interaction of the antimicrobial peptide with the membrane depends on peptide charge, hydrophobicity, membrane composition, etc. Therefore, to get insights into the mechanisms of membrane disruption, it is useful to study the model membrane, as biological membranes are complex and regulated by various other proteins, cholesterol, etc. In the present review, we will primarily describe the interaction of antimicrobial peptides with phospholipid membranes, which mimic the bacterial membrane, in view of understanding the mechanism of action, various factors affecting their activity, application prospects in drug therapeutics, etc. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are excellent promising candidates for biomedical applications owing to their structural properties, high biocompatibility, good biodegradability, and functional diversity. Unlike conventional antibiotics, AMPs have been shown to have broad‐spectrum antimicrobial activity toward Gram‐positive/negative bacteria, as well as antifungal and antiviral activity. These peptides have also been found to be cytotoxic to sperm and cancer cells. A range of AMPs has been isolated from various organisms, such as bacteria, fungi, plants, and animals. This review summarizes the latest studies on AMPs, covering their isolation, purification, and characterization as well as their potential biomedical applications and beyond. [ABSTRACT FROM AUTHOR]

The emergence of antibiotic-resistant Acinetobacter baumannii (A. baumannii) is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant A. baumannii, serving as the last line of defense. However, reports of colistin-resistant strains of A. baumannii have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens. To resist colistin, A. baumannii has developed several mechanisms. These include the loss of outer membrane lipopolysaccharides (LPSs) due to mutation of LPS biosynthetic genes, modification of lipid A (a constituent of LPSs) structure through the addition of phosphoethanolamine (PEtN) moieties to the lipid A component by overexpression of chromosomal pmrCAB operon genes and eptA gene, or acquisition of plasmid-encoded mcr genes through horizontal gene transfer. Other resistance mechanisms involve alterations of outer membrane permeability through porins, the expulsion of colistin by efflux pumps, and heteroresistance. In response to the rising threat of colistin-resistant A. baumannii, researchers have developed various treatment strategies, including antibiotic combination therapy, adjuvants to potentiate antibiotic activity, repurposing existing drugs, antimicrobial peptides, nanotechnology, photodynamic therapy, CRISPR/Cas, and phage therapy. While many of these strategies have shown promise in vitro and in vivo, further clinical trials are necessary to ensure their efficacy and widen their clinical applications. Ongoing research is essential for identifying the most effective therapeutic strategies to manage colistin-resistant A. baumannii. This review explores the genetic mechanisms underlying colistin resistance and assesses potential treatment options for this challenging pathogen. [ABSTRACT FROM AUTHOR]

Scheme of putative synergism between a cationic α-helix lipopeptide with conventional antibiotics. Minocycline (MC) is a protein production inhibitor, so it must get inside the bacterial cell to display antimicrobial activity. In the example, the resistance mechanism of this Gram-negative bacteria is an efflux pump, which pumps the antibiotic outside the cell. The lipopeptide would permeabilize the membrane thus producing the income of more antibiotic molecules to the cytoplasm, where they could finally get the target. [Display omitted] Antimicrobial resistance (AMR) is fast becoming a major global challenge in both hospital and community settings as many current antibiotics and treatment processes are under the threat of being rendered less effective or ineffective. Synergistic combination of an antibiotic and an aiding agent with a different set of properties provides an important but largely unexploited option to 'repurpose' existing biomaterial's space while addressing issues of potency, spectrum, toxicity and resistance in early stages of antimicrobial drug discovery. This work explores how to combine tetracycline/minocycline (TC/MC) with a broad-spectrum antimicrobial lipopeptide that has been designed to improve the efficiency of membrane targeting and intramembrane accumulation, thereby enhancing antimicrobial efficacy. Experimental measurements of fractional inhibition concentration index (FICI) were undertaken from binary antibiotic-lipopeptide combinations. Most FICI values were found to be lower than 0.5 against both Gram-positive and Gram-negative bacterial strains studied including 3 AMR strains, revealing strong synergetic effects via favorable membrane-lytic interactions. The antimicrobial actions of this type of binary combinations are featured by the fast time-killing and high TC/MC uptake, benefited from effective membrane-lytic disruptions by the lipopeptide. This study thus provides an important mechanistic understanding of the combined antibiotic-lipopeptide approach to improve the therapeutic potential of conventional antibiotics by illustrating how amphiphilic lipopeptide-antibiotic combinations interact with biological membranes, providing a promising alternative to combat AMR through rational design of lipopeptide as an aiding agent. [ABSTRACT FROM AUTHOR]

Background: Warfarin interacts with antibacterials to prolong the prothrombin time international normalized ratio (PT-INR) and increase the risk of bleeding. Patients initiating warfarin therapy often undergo precise dosage adjustments; however, the clinical implications of these interactions with antibacterials remain unclear. This study aimed to clarify the effect of antibacterials on PT-INR during the warfarin induction phase. Methods: This was a retrospective, observational study. Patients who were newly treated with warfarin after cardiovascular surgery were included. The primary endpoint was the comparison of the maximum PT-INR and time in therapeutic range (TTR) after warfarin initiation between the antibacterial-treated (ABx) and non-treated (non-ABx) groups. Results: The maximum PT-INR was significantly higher in the ABx group (which included β-lactams, glycopeptides, quinolones, tetracyclines, and aminoglycosides) than in the non-ABx group (median [interquartile range] 2.37 [2.03–2.71] vs. 2.08 [1.93–2.33]; P = 0.005); however, the TTR did not differ significantly (65% [44–76] vs. 71% [43–85]; P = 0.150). The odds ratio for maximum PT-INR > 2.6 with antimicrobial therapy was 2.51 (95% confidence interval 1.21–5.21). Discussion: Antibacterial therapy was a risk factor for a maximum PT-INR >2.6. However, there was no association with the TTR, which is a marker of good outcomes. This was due to the strict warfarin dosing regimen according to the algorithm, which immediately and appropriately adjusted for PT-INR overexpansion. Conclusions: Antibacterials have been suggested to increase PT-INR during the induction phase of warfarin. However, with strict dose adjustments, the clinical impact on the PT-INR and TTR is likely limited. [ABSTRACT FROM AUTHOR]

Despite the high survival rates of dental implants, peri-implantitis is a prevalent complication. Peri-implantitis is related to biofilm that adheres to the surface of implants and causes peri-implant chronic inflammation and bone destruction. Different surface treatments have been proposed to prevent biofilm formation. The objective of this systematic review was analyzing different types of antimicrobial coatings and identifying the most effective one(s) to control bacterial colonization over extended periods of analysis. We performed a bibliographic search in Pubmed and Cochrane base of articles published after 2010 to answer, according to the PICO system, the following question: What is the most effective antibacterial surface coating for dental implants? Only papers including a minimum follow-up bacteria growth analysis for at least 48 h were selected. After selection, the studies were classified using the PRISMA system. A total of 40 studies were included. Three main categories of coatings were identified: Antibacterial peptides, synthetic antimicrobial molecules (polymers, antibiotics, ...), and metallic nanoparticles (silver). Antibacterial peptide coatings to modify dental implant surfaces have been the most studied and effective surface modification to control bacterial colonization over extended periods of incubation as they are highly potent, durable and biocompatible. However, more in vitro and pre-clinical studies are needed to assess their true potential as a technology for preventing peri-implant infections. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are a promising solution for treating antibiotic‐resistant pathogens. However, efficient generation of diverse AMPs without prior knowledge of peptide structures or sequence alignments remains a challenge. Here, ProT‐Diff is introduced, a modularized deep generative approach that combines a pretrained protein language model with a diffusion model for the de novo generation of AMPs sequences. ProT‐Diff generates thousands of AMPs with diverse lengths and structures within a few hours. After silico physicochemical screening, 45 peptides are selected for experimental validation. Forty‐four peptides showed antimicrobial activity against both gram‐positive or gram‐negative bacteria. Among broad‐spectrum peptides, AMP_2 exhibited potent antimicrobial activity, low hemolysis, and minimal cytotoxicity. An in vivo assessment demonstrated its effectiveness against a drug‐resistant E. coli strain in acute peritonitis. This study not only introduces a viable and user‐friendly strategy for de novo generation of antimicrobial peptides, but also provides potential antimicrobial drug candidates with excellent activity. It is believed that this study will facilitate the development of other peptide‐based drug candidates in the future, as well as proteins with tailored characteristics. [ABSTRACT FROM AUTHOR]

For the first time, N-modified analogues of VV-hemorphin-5 (Valorphin) were synthesised and conjugated with three different 4-substitured-1,8-naphthalimides (H-NVal without substituent, Cl-NVal with chloro-substituent, and NO2-NVal with nitro-substituent). Cotton fabric was modified with these peptides by soaking it in their ethanol solution, and the colourimetric properties of the obtained fabric were measured. The fluorescent analysis shows that peptide immobilisation on a solid matrix as fabric decreases the molecule flexibility and spectrum maxima shift bathocromically with the appearance of a vibrational structure. The peptides' contact antimicrobial activity, and the resulting fabrics, have been investigated against model Gram-positive B. cereus and Gram-negative P. aeruginos bacteria. For the first time, the influence of light on bacterial inactivation was investigated by antibacterial photodynamic therapy of similar peptides. Slightly more pronounced activity in liquid media and after deposition on the cotton fabric was obtained for the peptide containing 4-nitro-1,8-naphthalimide compared to the other two peptides. Immobilisation of a peptide on the surface of fibres reduces their antimicrobial activity since their mobility is essential for good contact with bacteria. Cotton fabrics can be used in medical practice to produce antibacterial dressings and materials. [ABSTRACT FROM AUTHOR]

Peptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these issues by using bacteria to produce and deliver therapeutic compounds at the body site of use. A key advantage of this technology is the possibility to control drug delivery within the body in real time using genetic switches. However, the performance of such genetic switches suffers when used to control drugs that require post-translational modifications or are toxic to the host. In this study, these challenges were experienced when attempting to establish a thermal switch for the production of a ribosomally synthesized and post-translationally modified peptide antibiotic, darobactin, in probiotic E. coli. These challenges were overcome by developing a thermo-amplifier circuit that combined the thermal switch with a T7 RNA Polymerase. Due to the orthogonality of the Polymerase, this strategy overcame limitations imposed by the host transcriptional machinery. This circuit enabled production of pathogen-inhibitory levels of darobactin at 40 °C while maintaining leakiness below the detection limit at 37 °C. Furthermore, the thermo-amplifier circuit sustained gene expression beyond the thermal induction duration such that with only 2 h of induction, the bacteria were able to produce pathogen-inhibitory levels of darobactin. This performance was maintained even in physiologically relevant simulated conditions of the intestines that include bile salts and low nutrient levels. [ABSTRACT FROM AUTHOR]

Summary Crop diseases cause significant quality and yield losses to global crop products each year and are heavily controlled by chemicals along with very limited antibiotics composed of small molecules. However, these methods often result in environmental pollution and pest resistance, necessitating the development of new bio‐controlling products to mitigate these hazards. To identify effective antimicrobial peptides (AMPs) considered as potential sources of future antibiotics, AMPs were screened from five bacterial strains showing antagonism against a representative phytopathogenic fungus (Rhizoctonia Solani) through the Bacillus subtilis expression system, which has been developed for identifying bacterial AMPs by displaying autolysis morphologies. A total of 5000 colonies were screened, and five displaying autolysis morphologies showed antagonism against R. solani. A novel AMP with the strongest antagonism efficiency was determined and tentatively named HR2‐7, which is composed of 24 amino acids with an alpha‐helical structure. HR2‐7 has strong and broad‐spectrum antimicrobial activity, tested against 10 g‐positive and ‐negative bacteria and four phytopathogenic fungi by contact culture in plates with minimal lethal concentrations of 4.0 μM. When applied as purified peptide or in fermented B. subtilis culture solution, HR2‐7 showed strong controlling efficiency on plants against diverse fungal and bacterial pathogens. Based on current understanding, HR2‐7 is recognized as the first AMP derived from an agricultural antagonistic bacterium. It exhibits wide‐ranging and notable antimicrobial efficacy, offering a supplementary approach for managing plant diseases, in addition to conventional chemical pesticides and antibiotics. [ABSTRACT FROM AUTHOR]

The frequent and irrational use of antibiotics by humans has led to the escalating rise of antimicrobial resistance (AMR) with a high rate of morbidity-mortality worldwide, which poses a challenge to the development of effective treatments. A large number of host defense peptides from different organisms have gained interest due to their broad antibacterial spectrum, rapid action, and low target resistance, implying that these natural sources might be a new alternative to antimicrobial drugs. As important effectors of prey capture, defense against other animal attacks, and competitor deterrence, scorpion venoms have been developed as important candidate sources for modern drug development. With the rapid progress of bioanalytical and high throughput sequencing techniques, more and more scorpion-venom-derived peptides, including disulfide-bridged peptides (DBPs) and non-disulfide-bridged peptides (NDBPs), have been recently identified as having massive pharmacological activities in channelopathies, pathogen infections, and cancer treatments. In this review, we summarize the molecular diversity and corresponding structural classification of scorpion venom peptides with antibacterial, antifungal, and/or antiparasitic activity. We also aim to improve the understanding of the underlying mechanisms by which scorpion-venom-derived peptides exert these antimicrobial functions, and finally highlight their key aspects and prospects for antimicrobial therapeutic or pharmaceutical application. [ABSTRACT FROM AUTHOR]

Background/Objectives: Antimicrobial peptides are essential molecules in the innate immunity of various organisms and possess a broad spectrum of antimicrobial, antitumor, and immunomodulatory activities. Due to their multifunctionality, they are seen as an alternative for controlling bacterial infections. Although conventional antibiotics have improved health worldwide, their indiscriminate use has led to the emergence of resistant microorganisms. To discover new molecules with antimicrobial activity that could overcome the limitations of traditional antibiotics, this study aimed to identify antimicrobial peptides in Ambystoma mexicanum. Methods: In this study, hypothetical proteins encoded in the Ambystoma mexicanum transcriptome were predicted. These proteins were aligned with peptides reported in the Antimicrobial Peptide Database (APD3) using the Fasta36 program. After identifying peptide sequences with potential antibacterial activity, their expression was confirmed through conventional polymerase chain reaction (PCR) and then chemically synthesized. The antibacterial activity of the synthesized peptides was evaluated against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922. Results: A new antimicrobial peptide named AXOTL-13 was identified. AXOTL-13 is an amphipathic cationic alpha-helical peptide with the ability to inhibit the growth of Escherichia coli without causing hemolysis in red blood cells, with its action likely directed at the membrane, as suggested by morphological changes observed through scanning electron microscopy. Conclusions: This research is pioneering in evaluating the activity of antimicrobial peptides present in Ambystoma mexicanum and in specifically identifying one of these peptides. The findings will serve as a reference for future research in this field. [ABSTRACT FROM AUTHOR]

Chronic wounds can develop as a result of prolonged inflammation during the healing process, which can happen due to bacterial infection. Therefore, preventing infection and controlling inflammation can accelerate wound healing. Antimicrobial peptides have different protective properties in addition to antimicrobial activity. Some of these activities include the stimulation of cytokine or chemokine synthesis, the facilitation of chemotaxis and cell proliferation, the acceleration of cell proliferation, the induction of anti-inflammatory responses, and the promotion of wound repair. This study aimed to assess the wound healing potential of a novel in silico-designed antimicrobial peptide. Then, its anti-inflammatory activity was investigated by measuring the level of tumor necrosis factor-α (TNF-α) and transforming growth factor beta (TGF-β) as indicators of the wound healing process. In addition, the influence of the peptide on cell migration was evaluated by a scratch test on human dermal fibroblasts (HDF) and HaCaT cells as a human epidermal keratinocyte cell line. The results showed that our new peptide could act well in inhibiting TNF-α over-secretion while increasing the expression of TGF-β as an anti-inflammatory factor. This peptide showed a significant potential to stimulate HDF and HaCaT cell migration and proliferation. Therefore, using this peptide as an anti-inflammatory component of wound dressings may be promising. • A novel antimicrobial peptide was designed from Cathelicidine-2, named as mCHTL (131-140). • The mCHTL (131-140) could inhibit TNF-α over-secretion. • The mCHTL (131-140) could increase the TGF-β expression. • The mCHTL (131-140) could stimulate HDF and HaCaT cells migration and proliferation. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) from amphibians represent a promising source of novel antibacterial agents due to their potent and broad-spectrum antimicrobial activity, which positions them as valid alternatives to conventional antibiotics. This review provides a comprehensive analysis of the mechanisms through which amphibian-derived AMPs exert their effects against bacterial pathogens. We focus on the identification of bacterial protein targets implicated in the action of these peptides and on biological processes altered by the effect of AMPs. By examining recent advances in countering multidrug-resistant bacteria through multi-omics approaches, we elucidate how AMPs interact with bacterial membranes, enter bacterial cells, and target a specific protein. We discuss the implications of these interactions in developing targeted therapies and overcoming antibiotic resistance (ABR). This review aims to integrate the current knowledge on AMPs' mechanisms, identify gaps in our understanding, and propose future directions for research to harness amphibian AMPs in clinical applications. [ABSTRACT FROM AUTHOR]

Oh-defensin, an antimicrobial peptide, extracted from the venom of Ornithoctonus hainana , potently inhibited fungi and Gram-negative bacteria but showed limited antibacterial potency against Gram-positive bacteria via an unknown mechanism. In this study, a recombinant peptide termed as 3×Oh-defensin-HA-6×His composed of three repeats of Oh-defensin followed by hemagglutinin (HA) and six histidine (6×His) double tags was expressed in Chlamydomonas reinhardtii. The bacteriostatic activity of 3×Oh-defensin-HA-6×His certified against both Gram-negative and Gram-positive bacteria was confirmed, with minimum inhibitory concentration (MIC) between 10 and 80 µg/mL. The minimum bactericidal concentration (MBC) was determined to range from 1× to 2×MIC. In addition, 3×Oh-defensin-HA-6×His exhibited resistance to temperature shocks, extreme pH, and proteinase digestion and it was biologically safe because it displayed low cytotoxicity and hemolysis. In addition, scanning electron microscopy (SEM) and propidium iodide (PI) staining revealed that 3×Oh-defensin-HA-6×His caused the destruction of the bacterial cell membrane, which effectively inhibited bacterial growth. In summary, our findings suggest that green algae-derived 3×Oh-defensin-HA-6×His holds significant promise as a potential alternative to conventional antibiotics in the future. [Display omitted] • A triple Oh-defensin (3×Oh-defensin-HA-6×His) was stably expressed in green algae. • 3×Oh-defensin-HA-6×His inhibits the growth of a broad-spectrum bacteria. • 3×Oh-defensin-HA-6×His is thermostable and resists on extreme pH and proteinase digestion. • 3×Oh-defensin-HA-6×His is biologically safe. • 3×Oh-defensin-HA-6×His inhibits bacterial growth by disrupting the bacterial cell membrane. [ABSTRACT FROM AUTHOR]

The control of fungal and bacterial plant diseases mainly relies on the application of mineral and chemical fungicides/bactericides, which are considered to be environmental pollutants and toxic to humans. Moreover, the prolonged use of bactericides and antibiotics has led to the development of resistance among pathogens, as well as an increase in environmental and health threats. Therefore, the development of non-toxic and non-polluting treatments to control plant diseases has been the focus of extensive research in agriculture. Synthetic antimicrobial peptides have recently received extensive attention as the potential alternatives to other conventional methods in terms of their strong broad-spectrum antimicrobial activity. In vitro assays using various chemically synthesized peptides showed that the broad-spectrum peptide thanatin derived from the spined soldier bug (Podisus maculiventris (Say)) had the greatest potential for eliminating aflatoxigenic fungi. However, the antibacterial effect of thanatin against bacterial plant pathogens was less studied so far. The thanatin encoding sequence was codon optimized for expression in Pichia pastoris. This coding sequence cloned into P. pastoris expression vector pPICZαA and used for synthetizing the recombinant thanatin. Then, antibacterial activities of the constructed peptide were studied under in vitro and in vivo condition. The result showed that, all construction, cloning and expression processes were successfully performed in yeast. The results of the MIC and MBC tests showed that the growth rate of the majority of bacterial plant pathogens including gram-negative and gram-positive bacteria was inhibited by recombinant thanatin under in vitro conditions. MIC values for different bacterial isolates ranged from 0.016 to 2.048, while the MBC values for the same bacterial isolates were determined to be between 0.064 and 4.096 μg/mL. These amounts were significantly lower than the MIC and MBC values obtained by applying copper oxychloride. The application of 4.09 μg/mL of recombinant thanatin against rice leaf blight splendidly controlled this bacterial disease under greenhouse conditions. However, this promising antimicrobial peptide requires further investigation for the development of novel molecules for the control of plant pathogens. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides take a specific position in the field of antibiotics (ATBs), however, from a large number of available molecules only a few of them were approved and are used in clinics. These therapeutic modalities play a crucial role in the management of diseases caused by multidrug‐resistant bacterial pathogens and represent the last‐line therapy for bacterial infections. Therefore, there is a demand for a rationale use of such ATBs based on optimization of the dosing strategy to minimize the risk of resistance and ensure the sustainable efficacy of the drug in real clinical practice. Therapeutic drug monitoring, as a measurement of drug concentration in the body fluids or tissues, results in the optimization of the patient´s medication and therapy outcome. This strategy is beneficial and could result in tailored therapy for different types of infection and the prolongation of the use and efficacy of ATBs in hospitals. This review paper provides an actual overview of approved antimicrobial peptides used in clinical practice and covers current trends in their analysis by convenient and advanced methodologies used for their identification and/or quantitation in biological matrices for therapeutic drug monitoring purposes. Special emphasis is given to the methods with perspective clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: The persistence of antibiotic resistance has incited a strong interest in the discovery of agents with novel antimicrobial mechanisms. The direct killing of multidrug-resistant bacteria by cationic antimicrobial peptides (AMPs) underscores their importance in the fight against infections associated with antibiotic resistance. Despite a vast body of AMP literature demonstrating a plurality in structural classes, AMP engineering has been largely skewed toward peptides with idealized amphipathic helices (H-amphipathic). In contrast to helical amphipathicity, we designed a series of peptides that display the amphipathic motifs in the primary structure. We previously developed a rational framework for designing AMP libraries of H-amphipathic peptides consisting of Arg, Trp, and Val (H-RWV, with a confirmed helicity up to 88% in the presence of membrane lipids) tested against the most common MDR organisms. Methods: In this study, we re-engineered one of the series of the H-RWV peptides (8, 10, 12, 14, and 16 residues in length) to display the amphipathicity in the primary structure by side-by-side (linear) alignment of the cationic and hydrophobic residues into the 2 separate linear amphipathic (L-amphipathic) motifs. We compared the 2 series of peptides for antibacterial activity, red blood cell (RBC) lysis, killing and membrane-perturbation properties. Results: The L-RWV peptides achieved the highest antibacterial activity at a minimum length of 12 residues (L-RWV12, minimum optimal length or MOL) with the lowest mean MIC of 3–4 µM, whereas the MOL for the H-RWV series was reached at 16 residues (H-RWV16). Overall, H-RWV16 displayed the lowest mean MIC at 2 µM but higher levels of RBC lysis (25–30%), while the L-RWV series displayed minor RBC lytic effects at the test concentrations. Interestingly, when the S. aureus strain SA719 was chosen because of its susceptibility to most of the peptides, none of the L-RWV peptides demonstrated a high level of membrane perturbation determined by propidium iodide incorporation measured by flow cytometry, with <50% PI incorporation for the L-RWV peptides. By contrast, most H-RWV peptides displayed almost up to 100% PI incorporation. The results suggest that membrane perturbation is not the primary killing mechanism of the L-amphipathic RWV peptides, in contrast to the H-RWV peptides. Conclusions: Taken together, the data indicate that both types of amphipathicity may provide different ideal pharmacological properties that deserve further investigation. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) poses a serious threat to human health worldwide. It is now more challenging than ever to introduce a potent antibiotic to the market considering rapid emergence of antimicrobial resistance, surpassing the rate of antibiotic drug discovery. Hence, new approaches need to be developed to accelerate the rate of drug discovery process and meet the demands for new antibiotics, while reducing the cost of their development. Machine learning holds immense promise of becoming a useful tool, especially since in the last two decades, exponential growth has occurred in computational power and biological big data analytics. Recent advancements in machine learning algorithms for drug discovery have provided significant clues for potential antibiotic classes. Apart from discovery of new scaffolds, the machine learning protocols will significantly impact prediction of AMR patterns and drug metabolism. In this review, we outline power of machine learning in antibiotic drug discovery, metabolic fate, and AMR prediction to support researchers engaged and interested in this field. [ABSTRACT FROM AUTHOR]

Equine endometritis is one of the main causes of subfertility in the mare. Unraveling the molecular mechanisms involved in this condition and pinpointing proteins with biomarker potential could be crucial in both diagnosing and treating this condition. This study aimed to identify the endometritis-induced changes in the endometrial proteome in mares and to elucidate potential biological processes in which these proteins may be involved. Secondly, biomarkers related to bacterial endometritis (BE) in mares were identified. Uterine lavage fluid samples were collected from 28 mares (14 healthy: negative cytology and culture, and no clinical signs and 14 mares with endometritis: positive cytology and culture, in addition to clinical signs). Proteomic analysis was performed with a UHPLC-MS/MS system and bioinformatic analysis was carried out using Qlucore Omics Explorer. Gene Ontology enrichment and pathway analysis (PANTHER and KEGG) of the uterine proteome were performed to identify active biological pathways in enriched proteins from each group. Quantitative analysis revealed 38 proteins differentially abundant in endometritis mares when compared to healthy mares (fold changes >4.25, and q-value = 0.002). The proteins upregulated in the secretome of mares with BE were involved in biological processes related to the generation of energy and REDOX regulation and to the defense response to bacterium. A total of 24 biomarkers for BE were identified using the biomarker workbench algorithm. Some of the proteins identified were related to the innate immune system such as isoforms of histones H2A and H2B involvement in neutrophil extracellular trap (NET) formation, complement C3a, or gelsolin and profilin, two actin-binding proteins which are essential for dynamic remodeling of the actin cytoskeleton during cell migration. The other group of biomarkers were three known antimicrobial peptides (lysosome, equine cathelicidin 2 and myeloperoxidase (MPO)) and two uncharacterized proteins with a high homology with cathelicidin families. Findings in this study provide the first evidence that innate immune cells in the equine endometrium undergo reprogramming of metabolic pathways similar to the Warburg effect during activation. In addition, biomarkers of BE in uterine fluid of mares including the new proteins identified, as well as other antimicrobial peptides already known, offer future lines of research for alternative treatments to antibiotics. • Mares with bacterial endometritis exhibited a significantly higher relative abundance of endometrial proteins compared to clinically healthy mares. • The proteins upregulated in the secretome of mares with bacterial endometritis were involved in biological processes related to the generation of energy and REDOX regulation and to the defense response to bacterium (neutrophil extracellular trap (NET) formation pathway). • A total of 24 biomarkers for bacterial endometritis were identified. Some of the proteins identified were related to the innate immune system such as isoforms of histones H2A and H2B, complement C3a, or gelsolin and profilin. The other group of biomarkers were three known antimicrobial peptides (lysosome, equine cathelicidin 2 and MPO) and two uncharacterized proteins with a high homology with cathelicidin families. [ABSTRACT FROM AUTHOR]

The cell wall is an indispensable element of bacterial cells and a long-known target of many antibiotics. Penicillin, the first discovered beta-lactam antibiotic inhibiting the synthesis of cell walls, was successfully used to cure many bacterial infections. Unfortunately, pathogens eventually developed resistance to it. This started an arms race, and while novel beta-lactams, either natural or (semi)synthetic, were discovered, soon upon their application, bacteria were developing resistance. Currently, we are facing the threat of losing the race since more and more multidrug-resistant (MDR) pathogens are emerging. Therefore, there is an urgent need for developing novel approaches to combat MDR bacteria. The cell wall is a reasonable candidate for a target as it differentiates not only bacterial and human cells but also has a specific composition unique to various groups of bacteria. This ensures the safety and specificity of novel antibacterial agents that target this structure. Due to the shortage of low-molecular-weight candidates for novel antibiotics, attention was focused on peptides and proteins that possess antibacterial activity. Here, we describe proteinaceous agents of various origins that target bacterial cell wall, including bacteriocins and phage and bacterial lysins, as alternatives to classic antibiotic candidates for antimicrobial drugs. Moreover, advancements in protein chemistry and engineering currently allow for the production of stable, specific, and effective drugs. Finally, we introduce the concept of selective targeting of dangerous pathogens, exemplified by staphylococci, by agents specifically disrupting their cell walls. [ABSTRACT FROM AUTHOR]

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses an escalating threat to human health, necessitating the development of novel antimicrobial agents capable of addressing challenges posed by antibiotic-resistant bacteria. Thanatin, a 21-amino acid β-hairpin insect antimicrobial peptide featuring a single disulfide bond, exhibits broad-spectrum antibacterial activity, particularly effective against multidrug-resistant strains. The outer membrane biosynthesis system is recognized as a critical vulnerability in antibiotic-resistant bacteria, which thanatin targets to exert its antimicrobial effects. This peptide holds significant promise for diverse applications. This review begins with an examination of the structure–activity relationship and synthesis methods of thanatin. Subsequently, it explores thanatin's antimicrobial activity, detailing its various mechanisms of action. Finally, it discusses prospective clinical, environmental, food, and agricultural applications of thanatin, offering valuable insights for future research endeavors. [ABSTRACT FROM AUTHOR]

Bacterial infections are the most important cause of severe diseases. Antibiotics are the only major option to cure these infections. Most of the bacteria (approximately 90 %) have an extracellular polymeric substance layer forming a biofilm that allows them to resist the antimicrobial agents. It enables them to develop resistance against multiple drugs. As it is a tedious task to develop novel antimicrobial agents, there is a serious need to adopt alternative strategies. To counter the multidrug resistance in the bacteria, antimicrobial peptides have been developed and used. Antimicrobial peptides are potent antibiofilm agents possessing a promising broad spectrum of activity for the treatment of a variety of infections caused by bacteria, viruses and fungi. However, some of these peptides have a very short half-life in different species of microorganisms. Some antimicrobial peptides even produce toxic effects. Hence, there is a need to continuously develop safe and effective peptide analogues to be used as potential antibiofilm agents. The present review highlights the mechanism of the development of resistance towards antimicrobial agents and the role of antimicrobial peptides as antibiofilm agents in combating this resistance with a critical analysis of their benefits and limitations. In addition, an attempt has been made to review the latest developments on antimicrobial peptides along with their applications and patents published/granted ther eon. [ABSTRACT FROM AUTHOR]

Introduction: High-risk febrile neutropenia (FN) is one of the main causes of morbidity and mortality in onco-hematology. The initiation of empirical antibiotic therapy is an emergency that can change the prognosis of some patients. Given the emergence of increasingly resistant Gram-positive bacteremia, glycopeptides, as an empirical treatment, have an important place in the management of high-risk FN. The aim of this study is to evaluate the appropriateness of glycopeptide prescription in high-risk FN patients. Methods: This study was conducted in the Hematology Department of Fattouma Bourguiba University Hospital of Monastir, Tunisia. Patients with high-risk FN were enrolled during the period between January 1 and December 31, 2020. Results: Of the 29 patients included in this study, 88 FN episodes were noted of which 39 episodes treated with glycopeptides were evaluated. Twenty-four febrile episodes were empirically treated with glycopeptides (27.3%) of which 17 prescriptions (70.8%) were appropriate according to the European Conference on Infection in Leukemia and the Infectious Diseases Society of America recommendations. A therapeutic escalation using glycopeptides was noted in 17% of cases and appropriately opted in 6 FN episodes (40%). Conclusion: Prescriptions of glycopeptides were appropriate according to the international recommendations in 71% of the empirical prescriptions and in 40% of the therapeutic escalation using glycopeptides. In high-risk FN episodes, glycopeptides prescriptions should be rationalized and limited to the indications detailed in the international guidelines to control the emergence of multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]

Antibiotics are the super drugs that have revolutionized modern medicine by curing many infectious diseases caused by various microbes. They efficiently inhibit the growth and multiplication of the pathogenic microbes without causing adverse effects on the host. However, prescribing suboptimal antibiotic and overuse in agriculture and animal husbandry have led to the emergence of antimicrobial resistance, one of the most serious threats to global health at present. The efficacy of a new antibiotic is high when introduced; however, a small bacterial population attains resistance gradually and eventually survives. Understanding the mode of action of these miracle drugs, as well as their interaction with targets is very complex. However, it is necessary to fulfill the constant need for novel therapeutic alternatives to address the inevitable development of resistance. Therefore, considering the need of the hour, this article has been prepared to discuss the mode of action and recent advancements in the field of antibiotics. Efforts has also been made to highlight the current scenario of antimicrobial resistance and drug repurposing as a fast-track solution to combat the issue. [ABSTRACT FROM AUTHOR]

Background: Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus, characterized by exfoliative toxin B, and its increasing resistance to conventional antibiotics necessitates the search for new therapeutic options. Aim: The study aimed to investigate the potential of traditional medicinal compounds (TMCs) as potential pharmaceuticals against SSSS using molecular-level research. Introduction: Staphylococcus aureus, commonly known as S. aureus, is the main cause of SSSS. These infections are a major concern for public health because they are becoming resistant to antibiotics. There is an urgent need for new medications to effectively fight against this infection. The main objective of this study was to assess the interaction between TMC compounds and S. aureus exfoliative toxins ETA and ETB utilizing computational approaches. Materials and Methods: The investigation selected TMC compounds based on their potential to combat S. aureus infections. To predict binding affinities with the ETB toxin, molecular docking simulations were performed using AutoDock and AutoDock Vina. In order to evaluate the stability and interaction dynamics with the toxins, the most promising compound was subjected to a 100 ns molecular dynamics simulation. Stability was evaluated through various methods. Results: Liquiritin showed the highest binding affinity, with a docking score of −7.6 kcal/mol. MD simulation confirmed the complex's stability, and the binding free energy of −17.76 kcal/mol indicated potent inhibitory activity against S. aureus ETB. Conclusion: Liquiritin, a TMC, effectively inhibits S. aureus toxins ETB, with promising potential for treating SSSS and antibiotic-resistant infections, requiring further research. [ABSTRACT FROM AUTHOR]

Escherichia coli is a common cause of urinary tract infections and has shown increasing resistance to available antimicrobial agents. Antimicrobial peptides, such as Pardaxin, offer a potential alternative to traditional antibiotics due to their ability to disrupt bacterial cell membranes through interaction with the lipid bilayer. This mode of action reduces the likelihood of resistance development compared to conventional antibiotics that target specific cellular processes. The objective of this study was to assess the antimicrobial efficacy of the Pardaxin peptide against both standard and clinical strains of E. coli. E. coli ATCC 25922 was used as the standard strain, and 20 samples derived from patients were included in the study. Isolation and identification of E. coli were performed using enrichment media, selective media, and biochemical tests. Bacterial cultures were conducted on Mueller-Hinton agar, and the antimicrobial effect of the Pardaxin peptide was assessed using classic disk diffusion tests. During the disk diffusion test, a distinct area of no growth was observed surrounding the Pardaxin disks for both the standard and clinical strains. In the microdilution test, the minimum inhibitory concentration (MIC) of Pardaxin was found to be 390 µg/ml for the clinical strain and 450 µg/ml for the standard strain. These concentrations are comparable to the 500 µg/ml concentration of erythromycin, indicating the antibacterial properties of Pardaxin against E. coli. The results of this study provide evidence for the antimicrobial properties of the Pardaxin peptide against both standard and clinical strains of E. coli. [ABSTRACT FROM AUTHOR]