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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]

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]

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: 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]

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]

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]

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]

The special issue of the European Physical Journal: Special Topics focuses on Biomimetic and Cellular Membranes, showcasing the interdisciplinary nature of research in this field. The issue includes 19 contributions covering topics such as membrane organization, theory and simulations, synthetic and cellular membrane processes, and the soft matter of life. Researchers explore phenomena related to biomembranes using various experimental and theoretical models, shedding light on the complexities of biological systems and the dynamics of organelles within the cytoplasm. [Extracted from the article]

AbstractWith antibiotic resistance on the rise, there is an urgent need for new antibacterial drugs and products to treat or prevent infection. Many such products in current use, for example human and veterinary antibiotics and antimicrobial food preservatives, were discovered and developed from nature. Natural selection acts on all living organisms and the presence of bacterial competitors or pathogens in an environment can favor the evolution of antibacterial adaptations. In this review, we ask if vultures, blow flies and other carrion users might be a good starting point for antibacterial discovery based on the selection pressure they are under from bacterial disease. Dietary details are catalogued for over 600 of these species, bacterial pathogens associated with the diets are described, and an overview of the antibacterial defenses contributing to disease protection is given. Biotechnological applications for these defenses are then discussed, together with challenges facing developers and possible solutions. Examples include use of (a) the antimicrobial peptide (AMP) gene sarcotoxin IA to improve crop resistance to bacterial disease, (b) peptide antibiotics such as serrawettin W2 as antibacterial drug leads, (c) lectins for targeted drug delivery, (d) bioconversion-generated chitin as an antibacterial biomaterial, (e) bacteriocins as antibacterial food preservatives and (f) mutualistic microbiota bacteria as alternatives to antibiotics in animal feed. We show that carrion users encounter a diverse range of bacterial pathogens through their diets and interactions, have evolved many antibacterial defenses, and are a promising source of genes, molecules, and microbes for medical, agricultural, and food industry product development. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are a promising tool with which to fight rising antibiotic resistance. However, pathogenic bacteria are equipped with several AMP defense mechanisms, whose contributions to AMP resistance are often poorly defined. Here, we evaluate the genetic determinants of resistance to an insect AMP, cecropin B, in the opportunistic pathogen Enterobacter cloacae. Single-cell analysis of E. cloacae's response to cecropin revealed marked heterogeneity in cell survival, phenotypically reminiscent of heteroresistance (the ability of a subpopulation to grow in the presence of supra-MIC concentration of antimicrobial). The magnitude of this response was highly dependent on initial E. cloacae inoculum. We identified 3 genetic factors which collectively contribute to E. cloacae resistance in response to the AMP cecropin: The PhoPQ-two-component system, OmpT-mediated proteolytic cleavage of cecropin, and Rcs-mediated membrane stress response. Altogether, our data suggest that multiple, independent mechanisms contribute to AMP resistance in E. cloacae. Author summary: Antibiotics are losing their efficacy at an alarming rate, necessitating the development of novel strategies to combat bacterial infections. Antimicrobial peptides, which are essentially antibiotics produced by most animals, including humans, have been proposed as an alternative pathway to develop new clinical antimicrobials. However, similar to antibiotics, resistance against AMPs is widespread and varied, yet poorly-understood. Here, we have found that three major factors (the PhoPQ and Rcs cell envelope stress systems, and the protease OmpT) contribute to AMP resistance in the bacterium Enterobacter cloacae. We find that resistance is not equally distributed among a population, i.e. some cells are intrinsically more resistant than others. The number of resistant individuals in a population is determined by the three resistance factors we define here. Overall, our work provides new potential targets for the development of antibiotic compounds that may make AMPs work better against dangerous pathogens. [ABSTRACT FROM AUTHOR]

Polymer hydrogels find extensive application in biomedicine, serving specific purposes such as drug delivery, biosensing, bioimaging, cancer therapy, tissue engineering, and others. In response to the growing threat of bacterial infections and the escalating resistance to conventional antibiotics, this research introduces a novel injectable, self‐healing antimicrobial hydrogel comprising bioactive aldolized hyaluronic acid (AHA) and quaternized chitosan (QCS). This designed QCS/AHA hydrogel incorporates self‐assembling peptide nanofibers (PNFs) and small‐sized silver nanoparticles (AgNPs) for tailored functionality. The resulting hybrid QCS/AHA/PNF/AgNPs hydrogel demonstrates impressive rheological characteristics, broad‐spectrum antimicrobial efficacy, and high biocompatibility. Notably, its antimicrobial effectiveness against Escherichia coli and S. aureus surpasses 99.9%, underscoring its potential for treating infectious wounds. Moreover, the rheological analysis confirms its excellent shear‐thinning and self‐healing properties, enabling it to conform closely to irregular wound surfaces. Furthermore, the cytotoxicity assessment reveals its compatibility with human umbilical vein endothelial cells, exhibiting no significant adverse effects. The combined attributes of this bioactive QCS/AHA/PNF/AgNPs hydrogel position it as a promising candidate for antimicrobial applications and wound healing. [ABSTRACT FROM AUTHOR]

This case report details the challenging management of a 45-year-old male construction worker who suffered severe multiple injuries after a fall and subsequent collision with cement mixers. The patient presented with extensive injuries, including amputation, fractures and internal bleeding, leading to a state known as the 'triangle of death'. Despite the initial grim prognosis, evidenced by an ISS score of 28 and a mortality risk coefficient of 89.56%, the patient was successfully resuscitated and managed through a multidisciplinary approach. This included damage control resuscitation, emergency vascular interventions and targeted temperature management for brain protection. The patient's recovery highlights the effectiveness of comprehensive trauma management and the critical role of coordinated care in severe multi-trauma cases. [ABSTRACT FROM AUTHOR]

The recently identified natural product NOSO‐95A from entomopathogenic Xenorhabdus bacteria, derived from a biosynthetic gene cluster (BGC) encoding a non‐ribosomal peptide synthetase (NRPS), was the first member of the odilorhabdin class of antibiotics. This class exhibits broad‐spectrum antibiotic activity and inspired the development of the synthetic derivative NOSO‐502, which holds potential as a new clinical drug by breaking antibiotic resistance. While the mode of action of odilorhabdins was broadly investigated, their biosynthesis pathway remained poorly understood. Here we describe the heterologous production of NOSO‐95A in Escherichia coli after refactoring the complete BGC. Since the production titer was low, NRPS engineering was applied to uncover the underlying biosynthetic principles. For this, modules of the odilorhabdin NRPS fused to other synthetases were co‐expressed with candidate hydroxylases encoded in the BGC allowing the characterization of the biosynthesis of three unusual amino acids and leading to the identification of a prodrug‐activation mechanism by deacylation. Our work demonstrates the application of NRPS engineering as a blueprint to mechanistically elucidate large or toxic NRPS and provides the basis to generate novel odilorhabdin analogues with improved properties in the future. [ABSTRACT FROM AUTHOR]

The recently identified natural product NOSO‐95A from entomopathogenic Xenorhabdus bacteria, derived from a biosynthetic gene cluster (BGC) encoding a non‐ribosomal peptide synthetase (NRPS), was the first member of the odilorhabdin class of antibiotics. This class exhibits broad‐spectrum antibiotic activity and inspired the development of the synthetic derivative NOSO‐502, which holds potential as a new clinical drug by breaking antibiotic resistance. While the mode of action of odilorhabdins was broadly investigated, their biosynthesis pathway remained poorly understood. Here we describe the heterologous production of NOSO‐95A in Escherichia coli after refactoring the complete BGC. Since the production titer was low, NRPS engineering was applied to uncover the underlying biosynthetic principles. For this, modules of the odilorhabdin NRPS fused to other synthetases were co‐expressed with candidate hydroxylases encoded in the BGC allowing the characterization of the biosynthesis of three unusual amino acids and leading to the identification of a prodrug‐activation mechanism by deacylation. Our work demonstrates the application of NRPS engineering as a blueprint to mechanistically elucidate large or toxic NRPS and provides the basis to generate novel odilorhabdin analogues with improved properties in the future. [ABSTRACT FROM AUTHOR]

Objective: In this work, in order to optimize the structure of histidine-containing antifungal peptides with a "linear" type of amphipathicity (LTA), we carried out the synthesis and comparative screening of the antifungal activity of a series of histidine-containing SAMPs (F2H7, F2H10, F2H13, F2H16, H10, H10F2) with a "linear" type of amphipathicity that we constructed de novo. We also aimed to study their hemolytic properties, to assess their therapeutic index, and to compare the obtained results with similar data for the antifungal histidine-rich 12-mer peptide P113 (AKRHHGYKRKFH), a drug candidate known as PAC-113, one of the shortest and most active analogues of the natural antifungal histidine-rich peptide Hst 5. Methods: Peptides were synthesized by a solid phase method using a Fmoc-based strategy. To determine the antifungal activity of the peptides, we used the opportunistic fungus strain Candida albicans EMTK 34. The number of microorganisms (titer) in the suspension was determined by optical density at a wavelength of 595 nm. To determine the antifungal activity of the peptides, cell cultures were co-incubated with the studied peptides in 96-well plates. The cells were incubated with the drug for 24 h at 37°C. To assess the antifungal activity of the studied peptides, their minimum inhibitory concentrations (MIC50) were determined, i.e. such peptide concentration at which the growth of microorganisms was suppressed by 50%. To assess the toxicity of the peptides, their hemolytic activity was determined, which was tested against fresh human erythrocytes using a photometric method. To assess the selectivity of the action of peptides, the values of the minimum hemolytic concentration (MHC) of the peptides were determined and the values of their therapeutic index (TI) were calculated as the ratio of the minimum hemolytic concentration (MHC) to the MIC50 value. Results and Discussion: It was shown that the antifungal activity of the studied SAMPLTA increases with an increase in the number of histidine residues in their composition, reaching the maximum value for the histidine-containing peptide F2H16 (MIC50 = 1.0 µM). It has been shown that as the chain length of peptides increases, their hemolytic toxicity also increases. The TI values for these peptides were 233, 247, 79, and 60, respectively. It has been shown that, against C. albicans, histidine-containing SAMP-LTA derivatives with phenylalanine residues at the N-terminus of the peptide (F2H10) are less effective compared to similar peptides (H10F2) containing phenylalanine residues at the C-terminus. Among the studied peptides, the most active was the H10 peptide (MIC50 = 0.7 µM), which does not contain phenylalanine residues, which in its antifungal activity is not only more effective than all other histidine-containing peptides, including the F2H16 peptide with 16 histidine residues, but also 4– 5 times more effective than the antifungal peptide P113 (MIC50 = 3.4 µM), a short active fragment of natural Hst 5, well known from the literature. Among all the studied peptides, H10 and P113 have minimal (almost zero) values of hemolytic activity. However, due to its higher antifungal activity, the selectivity of the H10 peptide (TI > 1400) exceeds the selectivity of the P113 peptide (TI > 340) by more than 4 times. Conclusions: Thus, peptide H10, due to its high antifungal activity, low hemolytic toxicity and, accordingly, high therapeutic significance, can be used as a promising antifungal peptide drug. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are considered a promising alternative to conventional antibiotics to fight against the rapid evolution of antibiotic resistance. Other than their potent antimicrobial properties, AMP-based vesicles can be used as efficient drug-delivery vehicles. In the present study, we synthesized and characterized a new cyclic AMP, consisting of all-hydrophobic cores with antimicrobial activity against S. aureus. Interestingly, CycP undergoes supramolecular self-assembly, and self-assembled CycP (sCycP) vesicles are characterized under an electron microscope; however, these vesicles do not display antimicrobial activity. Next, sCycP vesicles are used in combination with SXT (sulfamethoxazole–trimethoprim) vesicles to check the drug loading and delivery capacity of sCycP vesicles to bacterial cell membranes. Interestingly, sCycP vesicles showed synergistic action with SXT vesicles and resulted in a significant reduction in MIC against S. aureus. Further, electron microscopy confirmed the membrane-specific killing mechanism of SXT-loaded sCycP vesicles. Additionally, CycP showed high binding affinities with the β-lactamase of S. aureus, which was one of its possible antimicrobial mechanisms of action. Overall, the results suggested that CycP is a novel self-assembled dual-action cyclic AMP with non-cytotoxic properties that can be used alone as an AMP or a self-assembled drug delivery vehicle for antibiotics to combat S. aureus infections. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis of breast cancer. Thiostrepton exerts anti-tumor activities against several cancers including TNBC. Herein we discussed the new molecular mechanisms of thiostrepton in TNBC. Thiostrepton inhibited MDA-MB-231 cell viability, accompanied by a decrease of c-FLIP and p-SMAD2/3. c-FLIP overexpression reduced the sensitivity of MDA-MB-231 cells to thiostrepton, while SMAD2/3 knockdown increased the sensitivity of MDA-MB-231 cells to thiostrepton. Moreover, c-FLIP overexpression significantly increased the expression and phosphorylation of SMAD2/3 proteins and vice versa. In conclusion, our study reveals c-FLIP/SMAD2/3 signaling pathway as a novel mechanism of antitumor activity of thiostrepton. [ABSTRACT FROM AUTHOR]

NLRP6 plays a crucial role in maintaining intestinal homeostasis by regulating the interaction between the intestinal mucosa and the microbiota. However, the impact of NLRP6 deficiency on intestinal damage following hematopoietic stem cell transplantation (HSCT) remains poorly understood. In this study, we established a syngeneic HSCT mouse model using C57BL/6 mice as donors and NLRP6-/- or C57BL/6 mice as recipients. Our findings revealed that NLRP6 deficiency had minimal influence on peripheral blood cell counts and splenic immune cell proportions in transplanted mice. However, it exacerbated pathological changes in the small intestine on day 14 post-transplantation, accompanied by increased proportions of macrophages, dendritic cells, and neutrophils. Furthermore, the NLRP6 deficiency resulted in elevated expression of MPO and CD11b, while reducing the levels mature caspase-1 and mature IL-1β in the intestine. Moreover, the NLRP6 deficiency disturbed the expression of apoptosis-related molecules and decreased the tight junction protein occludin. Notably, recipient mice with NLRP6 deficiency exhibited lower mRNA expression levels of antimicrobial genes, such as Reg3γ and Pla2g2a. The short-term increase in inflammatory cell infiltration caused by NLRP6 deficiency was associated with intestinal damage, increased apoptosis, reduced expression of antimicrobial peptides, and impaired intestinal repair. Taken together, our findings demonstrate that the loss of NLRP6 exacerbates post-transplantation intestinal damage in recipient mice. [ABSTRACT FROM AUTHOR]