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Klebsiella pneumoniae is a common pathogen capable of causing a wide range of infections. Antibiotic resistance complicates treatment of these infections significantly. We are comparing resistance levels and genotypes among two collections of K. pneumoniae clinical isolates from Alexandria Main University Hospital (AMUH). We used disc diffusion and Minimum Inhibitory Concentration (MIC) by microbroth dilution to assess resistance levels and performed whole genome sequencing (WGS) to describe multilocus sequence types (MLST) and resistance gene presence. Among a collection of 56 K. pneumoniae clinical isolates (19 from 2019 to 37 from 2021), multidrug resistance (MDR) was 33% and 10%, extended drug resistance (XDR) was 24% and 46% and pan-drug resistance (PDR) was 43% and 43%, respectively. We identified 15 MLST STs including two novel types (ST-6118 and ST-6119). ST-101 and ST-383 were common between the two collections; ST-101 was the most common genotype in 2019 (28.6%) and ST-147 was most common in 2021 (25%). Ampicillin/sulbactam, amikacin, cefepime, ceftriaxone and ertapenem MICs were significantly higher in 2021. Prevalence of aph(3') – Ia, aph(3')-VI, mphA was significantly higher in 2021. The increasing resistance levels and the persistence of some MDR/XDR genotypes is concerning. Understanding mechanisms of resistance will inform infection control and antimicrobial stewardship plans to prevent evolution and spread of XDR and PDR strains. [ABSTRACT FROM AUTHOR]

Background: The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii. Objectives: The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologicallybased pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii. Methods: A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices. Results: The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population. Conclusion: The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates. [ABSTRACT FROM AUTHOR]

Food-producing animals such as dairy cattle are potential reservoirs of antimicrobial resistance (AMR), with multidrug-resistant (MDR) organisms such as Escherichia coli observed in higher frequency in young calves compared to older cattle. In this study, we characterized the genomes of enteric MDR E. coli from pre-weaned dairy calves with and without diarrhea and evaluated the influence of host-level factors on genomic composition. Whole genome sequence comparative analysis of E. coli (n = 43) revealed substantial genomic diversity that primarily clustered by sequence type and was minimally driven by calf diarrheal disease status (healthy, diarrheic, or recovered), antimicrobial exposure, and dietary zinc supplementation. Diverse AMR genes (ARGs)-- including extended-spectrum beta-lactamase genes and quinolone resistance determinants--were identified (n = 40), with unique sets of ARGs co-occurring in gene clusters with large AMR plasmids IncA/C2 and IncFIB(AP001918). Zinc supplementation was not significantly associated with the selection of individual ARGs in E. coli, however analysis of ARG and metal resistance gene pairs identified positive associations between certain aminoglycoside, betalactam, sulfonamide, and trimethoprim ARGs with acid, tellurium and mercury resistance genes. Although E. coli in this study lacked the typical virulence factors of diarrheagenic strains, virulence genes overlapping with those in major pathotypes were identified. Among the 103 virulence genes detected, the highest abundance and diversity of genes corresponded to iron acquisition (siderophores and heme uptake). Our findings indicate that the host-level factors evaluated in this study were not key drivers of genomic variability, but that certain accessory genes in enteric MDR E. coli may be enriched. Collectively, this work provides insight into the genomic diversity and host-microbe interface of MDR E. coli from pre-weaned dairy calves. [ABSTRACT FROM AUTHOR]

AbstractBetter in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance. [ABSTRACT FROM AUTHOR]

Enterococcus spp. are isolated from infections of domestic animals and can present resistance to different antimicrobials. This study aimed to identify the main species of Enterococcus and determine the phenotypic resistance to antimicrobials of isolates of this bacterial genus obtained from dogs and cats admitted to a veterinary hospital in southern Brazil. A total of 57 Enterococcus spp. were isolated from different clinical samples (urine, feces, ears and skin) in domestic animals admitted to the hospital over a period of three years (2016 to 2019). MALDI-TOF results demonstrated the occurrence of Enterococcus faecium (39; 68.4%), Enterococcus faecalis (17; 29.8%) and Enterococcus avium (1; 1.8%). In an overall analysis, resistance was observed to the antimicrobials rifampicin (46; 80.7%), tetracycline and streptomycin (42; 73.7%), ampicillin and imipenem (41; 71.9%), erythromycin (39; 68.4%), gentamicin (38; 66.7%), ciprofloxacin (36; 63.2%), norfloxacin (32; 56.1%), nitrofurantoin (10; 17.5%) and chloramphenicol (9; 15.7%). None of the Enterococcus spp. showed resistance to vancomycin and linezolid. Multidrug resistance (MDR) was detected in 45 (78.9%) isolates. In conclusion, E. faecium and E. faecalis with MDR are frequent in infections of hospitalized dogs and cats from southern Brazil. [ABSTRACT FROM AUTHOR]

Abstract Klebsiella pneumoniae is a common pathogen capable of causing a wide range of infections. Antibiotic resistance complicates treatment of these infections significantly. We are comparing resistance levels and genotypes among two collections of K. pneumoniae clinical isolates from Alexandria Main University Hospital (AMUH). We used disc diffusion and Minimum Inhibitory Concentration (MIC) by microbroth dilution to assess resistance levels and performed whole genome sequencing (WGS) to describe multilocus sequence types (MLST) and resistance gene presence. Among a collection of 56 K. pneumoniae clinical isolates (19 from 2019 to 37 from 2021), multidrug resistance (MDR) was 33% and 10%, extended drug resistance (XDR) was 24% and 46% and pan-drug resistance (PDR) was 43% and 43%, respectively. We identified 15 MLST STs including two novel types (ST-6118 and ST-6119 ). ST-101 and ST-383 were common between the two collections; ST-101 was the most common genotype in 2019 (28.6%) and ST-147 was most common in 2021 (25%). Ampicillin/sulbactam, amikacin, cefepime, ceftriaxone and ertapenem MICs were significantly higher in 2021. Prevalence of aph(3’) – Ia, aph(3’)-VI, mphA was significantly higher in 2021. The increasing resistance levels and the persistence of some MDR/XDR genotypes is concerning. Understanding mechanisms of resistance will inform infection control and antimicrobial stewardship plans to prevent evolution and spread of XDR and PDR strains.

Enterococcus spp. are isolated from infections of domestic animals and can present resistance to different antimicrobials. This study aimed to identify the main species of Enterococcus and determine the phenotypic resistance to antimicrobials of isolates of this bacterial genus obtained from dogs and cats admitted to a veterinary hospital in southern Brazil. A total of 57 Enterococcus spp. were isolated from different clinical samples (urine, feces, ears and skin) in domestic animals admitted to the hospital over a period of three years (2016 to 2019). MALDI-TOF results demonstrated the occurrence of Enterococcus faecium (39; 68.4%), Enterococcus faecalis (17; 29.8%) and Enterococcus avium (1; 1.8%). In an overall analysis, resistance was observed to the antimicrobials rifampicin (46; 80.7%), tetracycline and streptomycin (42; 73.7%), ampicillin and imipenem (41; 71.9%), erythromycin (39; 68.4%), gentamicin (38; 66.7%), ciprofloxacin (36; 63.2%), norfloxacin (32; 56.1%), nitrofurantoin (10; 17.5%) and chloramphenicol (9; 15.7%). None of the Enterococcus spp. showed resistance to vancomycin and linezolid. Multidrug resistance (MDR) was detected in 45 (78.9%) isolates. In conclusion, E. faecium and E. faecalis with MDR are frequent in infections of hospitalized dogs and cats from southern Brazil.

Pseudomonas aeruginosa, a Gram-negative bacterium, presents a substantial challenge in healthcare due to its adaptability and resistance. This study delves into its genotypic characteristics, focusing on ESBL and MBL genes. The prevalence of P. aeruginosa in nosocomial infections, the research aims to decipher resistance mechanisms crucial for tailored interventions. The study includes 170 non-repetitive clinical samples with protocols. Antibiotic susceptibility testing reveals diverse resistance patterns. Molecular detection of ESBL and MBL genes involves DNA isolation, PCR amplification, and gel electrophoresis. The study examined 170 P. aeruginosa samples, revealing gender-specific variations with 65.91% male and 34.09% female isolates. Antimicrobial testing displayed resistance in Ceftazidime (59%) and Ciprofloxacin (48%), while Ticarcillin-clavulanic acid showed promising sensitivity (58%). Molecular identification unveiled diverse resistance genes across sample types, emphasizing genetic complexity. The study underscores the urgency for targeted therapeutic interventions and novel antimicrobial strategies against P. aeruginosa infections. As antimicrobial resistance complexities persist, this research guides efforts toward a profound understanding of clinical interventions and strategic antimicrobial management.

Pseudomonas aeruginosa is a prevalent gram-negative pathogenic bacterium ubiquitous in natural environment. Aquatic environment of wastewater serves as reservoirs of this bacteria and their wide resistance phenomenon to a number of antibiotics is frequently increasing. This study was conducted to determine the prevalence of P. aeruginosa in 10 industrial waste water and 10 tannery waste water samples of whole Dhaka and 65% (13/20) water samples were found positive for P. aeruginosa which was confirmed by both biochemical test & BiologTM Microbial Identification System. Kirby Bauer disc diffusion method was applied for antimicrobial susceptibility testing and isolates showed resistance to most of the commercial antibiotics except neomycin, gentamycin, streptomycin, ciprofloxacin and nalidixic acid, hence confirmed the multidrug resistance (MDR) of P. aeruginosa in wastewater which is one of the life-threatening public health issues all over the world causing ineffectiveness of several antibiotics. So, it is recommended to make sure surface water or food samples not to be contaminated by this antibiotic resistant P. aeruginosa that might be transferred to animal and human. In these circumstances, not only the hygiene practice is the first and foremost prerequisite but also management practices with effective wastewater disposal system can also be a part of awareness. Additionally, appropriate and logical use of antibiotics must be applied to reduce the emergence of multidrug pathogens to environment.

Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin—a well-known hypoglycemic drug used in the treatment of type 2 diabetes—on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated. [ABSTRACT FROM AUTHOR]

The development of antibiotic resistance compromises the effectiveness of our most effective defenses against bacterial infections, presenting a threat to global health. To date, a large number of research articles exist in the literature describing the case reports associated with extensively drug-resistant (XDR) and multidrug-resistant (MDR) bacterial strains. However, these findings are scattered, making it time-consuming for researchers to locate promising results and there remains a need for a comparative study to compile these case reports from various geographical regions including the Kingdom of Saudi Arabia. Additionally, no study has yet been published that compares the genetic variations and case reports of MDR and XDR strains identified from Saudi Arabia, the Middle East, Central Europe, and Asian countries. This study attempts to provide a comparative analysis of several MDR and XDR case reports from Saudi Arabia alongside other countries. Furthermore, the purpose of this work is to demonstrate the genetic variations in the genes underlying the resistance mechanisms seen in MDR and XDR bacterial strains that have been reported in Saudi Arabia and other countries. To cover the gap, this comprehensive review explores the complex trends in antibiotic resistance and the growing risk posed by superbugs. We provide context on the concerning spread of drug-resistant bacteria by analyzing the fundamental mechanisms of antibiotic resistance and looking into individual case reports. In this article, we compiled various cases and stories associated with XDR and MDR strains from Saudi Arabia and various other countries including China, Egypt, India, Poland, Pakistan, and Taiwan. This review will serve as basis for highlighting the growing threat of MDR, XDR bacterial strains in Saudi Arabia, and poses the urgent need for national action plans, stewardship programs, preventive measures, and novel antibiotics research in the Kingdom. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance (AMR) poses a global health threat, with lower-middle-income countries bearing a disproportionate burden. Surveillance of AMR under a One Health framework is needed to elucidate the associations among clinical, animal, and environmental AMR. This review aimed to describe the state of AMR in Ghana, focusing on One Health. Method: This review utilized the PRISMA guidelines and major databases to systematically search and analyze AMR in Ghana published from 1 January 2014 to 1 May 2023. Results: Out of the 48 articles that met the inclusion criteria, 28 studies were conducted on humans, 14 studies involved animals, and 6 studies focused on the environment. A total of 48 different pathogens were identified across the human, animal, and environmental sectors, with the most common being Escherichia coli (67%, n = 32), Klebsiella spp. (52%, n = 25), Pseudomonas spp. (40%, n = 19), and Salmonella spp. (38%, n = 18). Generally, a high prevalence of antibiotic resistance was observed among various bacterial species across the sectors. These bacteria exhibited resistance to commonly used antibiotics, with resistance to ampicillin and tetracycline exceeding 80%, and multidrug resistance (MDR) ranging from 17.6% in Shigella spp. to 100% in Acinetobacter spp. Conclusion: This review reaffirms the significant challenge of AMR in Ghana, with a high prevalence observed in the human, animal, and environmental sectors. Key pathogens (e.g., Staphylococcus aureus and Escherichia coli) found across the sectors emphasize the urgent need for a One Health approach to tackle AMR in Ghana. [ABSTRACT FROM AUTHOR]

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood–brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer. [ABSTRACT FROM AUTHOR]

Integrons are one genetic factor that can contribute to the high prevalence of antibiotic resistance among Acinetobacter baumannii isolates and their spread. This research aimed to study the prevalence of class 1,2 and 3 integron in A. baumannii isolates and their relatedness to virulence factors of antibiotics resistance. Seventy clinical isolates of A.baumannii were isolated from several sources such as blood, urinary tract infection (UTI), sputum, urine, and cerebrospinal fluid (CSF). First, the isolates were identified and characterized according to certain morphology, cultural and biochemical tests. Second genotypic ally Identification of the isolates was confirmed by Polymerase chain reaction (PCR), which was performed by housekeeping gene 16sRNA and by (blaOxa 51gene) for A. baumannii species. The antimicrobial susceptibility technique was evaluated through disk diffusion methods. These isolates resistant to various antibiotics were analyzed for integron class I, II and III content and sequences of the amplification products by PCR. The findings showed that the predominant A. baumannii isolates were multidrug resistant and they were most resistant to 15 antibiotics. The higher resistance of A. baumannii to Gatifloxacin and lower resistance to polymyxin. Sixty clinical Multidrug resistance (MDR) isolates of A. baumannii had class I integron and five class III integron, but class II integron was not detected in the isolates. This revealed that the dissemination of MDR among A. baumannii may be associated with the presence of integrons class I and class III. These data indicate that integrons are gene cassettes containing antibiotic-resistance genes that play a major role in the virulence characteristics of MDR and Extensively-drug resistance (XDR) in Acinetobacter baumannii. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is a prevalent gram-negative pathogenic bacterium ubiquitous in natural environment. Aquatic environment of wastewater serves as reservoirs of this bacteria and their wide resistance phenomenon to a number of antibiotics is frequently increasing. This study was conducted to determine the prevalence of P. aeruginosa in 10 industrial waste water and 10 tannery waste water samples of whole Dhaka and 65% (13/20) water samples were found positive for P. aeruginosa which was confirmed by both biochemical test & BiologTM Microbial Identification System. Kirby Bauer disc diffusion method was applied for antimicrobial susceptibility testing and isolates showed resistance to most of the commercial antibiotics except neomycin, gentamycin, streptomycin, ciprofloxacin and nalidixic acid, hence confirmed the multidrug resistance (MDR) of P. aeruginosa in wastewater which is one of the life-threatening public health issues all over the world causing ineffectiveness of several antibiotics. So, it is recommended to make sure surface water or food samples not to be contaminated by this antibiotic resistant P. aeruginosa that might be transferred to animal and human. In these circumstances, not only the hygiene practice is the first and foremost prerequisite but also management practices with effective wastewater disposal system can also be a part of awareness. Additionally, appropriate and logical use of antibiotics must be applied to reduce the emergence of multidrug pathogens to environment. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa, a Gram-negative bacterium, presents a substantial challenge in healthcare due to its adaptability and resistance. This study delves into its genotypic characteristics, focusing on ESBL and MBL genes. The prevalence of P. aeruginosa in nosocomial infections, the research aims to decipher resistance mechanisms crucial for tailored interventions. The study includes 170 nonrepetitive clinical samples with protocols. Antibiotic susceptibility testing reveals diverse resistance patterns. Molecular detection of ESBL and MBL genes involves DNA isolation, PCR amplification, and gel electrophoresis. The study examined 170 P. aeruginosa samples, revealing gender-specific variations with 65.91% male and 34.09% female isolates. Antimicrobial testing displayed resistance in Ceftazidime (59%) and Ciprofloxacin (48%), while Ticarcillin-clavulanic acid showed promising sensitivity (58%). Molecular identification unveiled diverse resistance genes across sample types, emphasizing genetic complexity. The study underscores the urgency for targeted therapeutic interventions and novel antimicrobial strategies against P. aeruginosa infections. As antimicrobial resistance complexities persist, this research guides efforts toward a profound understanding of clinical interventions and strategic antimicrobial management. [ABSTRACT FROM AUTHOR]

Food-producing animals such as dairy cattle are potential reservoirs of antimicrobial resistance (AMR), with multidrug-resistant (MDR) organisms such as Escherichia coli observed in higher frequency in young calves compared to older cattle. In this study, we characterized the genomes of enteric MDR E. coli from pre-weaned dairy calves with and without diarrhea and evaluated the influence of host-level factors on genomic composition. Whole genome sequence comparative analysis of E. coli (n = 43) revealed substantial genomic diversity that primarily clustered by sequence type and was minimally driven by calf diarrheal disease status (healthy, diarrheic, or recovered), antimicrobial exposure, and dietary zinc supplementation. Diverse AMR genes (ARGs)—including extended-spectrum beta-lactamase genes and quinolone resistance determinants—were identified (n = 40), with unique sets of ARGs co-occurring in gene clusters with large AMR plasmids IncA/C2 and IncFIB(AP001918). Zinc supplementation was not significantly associated with the selection of individual ARGs in E. coli, however analysis of ARG and metal resistance gene pairs identified positive associations between certain aminoglycoside, beta-lactam, sulfonamide, and trimethoprim ARGs with acid, tellurium and mercury resistance genes. Although E. coli in this study lacked the typical virulence factors of diarrheagenic strains, virulence genes overlapping with those in major pathotypes were identified. Among the 103 virulence genes detected, the highest abundance and diversity of genes corresponded to iron acquisition (siderophores and heme uptake). Our findings indicate that the host-level factors evaluated in this study were not key drivers of genomic variability, but that certain accessory genes in enteric MDR E. coli may be enriched. Collectively, this work provides insight into the genomic diversity and host-microbe interface of MDR E. coli from pre-weaned dairy calves.

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin. [ABSTRACT FROM AUTHOR]

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites. [ABSTRACT FROM AUTHOR]

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3–10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] Tumor-associated macrophages (TAM) are the mainstay of immunosuppressive cells in the tumor microenvironment, and elimination of M2-type macrophages (M2-TAM) is considered as a potential immunotherapy. However, the interaction of breast cancer cells with macrophages hinders the effectiveness of immunotherapy. In order to improve the efficacy of triple-negative breast cancer (TNBC) therapy, strategies that simultaneously target the elimination of M2-TAM and breast cancer cells may be able to achieve a better therapy. LyP-SA/AgNP@Dox multifunctional nanoparticles were synthesized by electrostatic adsorption. They were characterized by particle size, potential and spectroscopy. And the efficacy of multifunctional nanoparticles was evaluated in 4 T1 cell lines and M2 macrophages, including their cell uptake intracellular reactive oxygen species (ROS) production and the therapeutic effect. Furthermore, based on the orthotopic xenotransplantation model of triple negative breast cancer, the biological distribution, fluorescence imaging, biosafety evaluation and combined efficacy evaluation of the nanoplatform were performed. We have successfully prepared LyP-SA/AgNP@Dox and characterized. Administering the nanosystem to 4 T1 tumor cells or M2 macrophages in culture induced accumulation of reactive oxygen species, destruction of mitochondria and apoptosis, and inhibited replication and transcription. Animal experiments demonstrated the nanoparticle had favorable targeting and antitumor activity. Our nanosystem may be useful for simultaneously inhibiting tumor and tumor-associated macrophages in breast cancer and, potentially, other malignancies. [ABSTRACT FROM AUTHOR]

Biofilm-forming methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen that adversely affects animal and human health. World Health Organization (WHO) has designated MRSA as a high-priority pathogen for research and development. In this study, we have investigated the pathogenic potential of MRSA recovered from mastitic milk of cow. The MRSA was initially characterized for coagulase, haemolytic and DNase activity followed by its biofilm forming ability. Further, an intravenous murine model of MRSA was developed using multiparameter approach comprising of disease activity score, viable bacterial count in blood and tissues; and, detection of biofilm mass in tissue. Infection was successfully established in mice following intravenous inoculation of 3 × 108 colony forming unit (CFU) per mL of MRSA. Fifty percent of MRSA-challenged mice died after infection whereas mice survived exhibited disease activity score >25. Significantly higher MRSA count was recorded in blood, liver and kidney of MRSA-challenged mice as compared to healthy mice (P <0.05). Gram staining revealed the presence of varied size of multiple clusters of Gram-positive biofilm mass in the liver and kidney of MRSA-challenged mice. This study on pathogenesis of MRSA in mice would be useful in not only controlling the MRSA infection, but also in the development of effective therapeutics. [ABSTRACT FROM AUTHOR]

Even though a wide variety of antimicrobial medications have been discovered and developed, multidrug resistance still poses a severe threat to public health and is continuously increasing mortality. Recently, a lot of research has focused on developing solutions to these problems. In this paper, we demonstrated how various antibiotics can be combined with antimicrobial substances like LAB and plant extracts to provide synergistic effects if each therapy concentrates on a different target or signalling pathway and acts via a different mechanism. MDR bacteria were isolated from chicken organs using standard methods, and they were confirmed using 16S RNA. In Al-Sharkia Governorate, Egypt, 100 different samples of chicken organs (including the breast, drumstick, liver, wings, skin, intestine, pins, giblets, heart, and legs) were taken at random from six different sites. Bacillus was the associated pathogenic bacteria obtained from the isolated chicken organs and was confirmed using molecular, biochemical, and microbiological techniques. The most efficient extracts that proved to have bacteriostatic and bactericidal properties against the highly resistant strains of pathogenic bacteria were found to be the LactoBacillus plantarum EMCC1027. The LAB applied in the study has excellent antibacterial properties and can be used as a safe substitute for antibiotics to inhibit the growth of the food-borne pathogens. [ABSTRACT FROM AUTHOR]

Multidrug resistance poses a danger to public health and steadily raises mortality, despite the discovery and development of a wide range of antimicrobial drugs. Developing practical solutions to address these problems has been the focus of many recent studies. In this work, we elucidate the way certain antibiotics, when coupled with other antimicrobial agents like plant extracts, can produce synergistic effects provided that each therapy targets a separate target or signaling pathway and functions via a different mechanism. Gas chromatography-mass spectrometry (GC-MS) and thin-layer chromatography (TLC) were used to identify bioactive metabolite extracts and purify plant extracts with active antibacterial qualities. The minimum inhibitory concentration (MIC) was determined using the broth microdilution method. Different 100 samples of meat (fresh, frozen Brazilian, Sudanese, and minced meat) and meat products such as pastrami, burgers, kofta, luncheon, and sausage were randomly collected from six (6) different locations in Al-Sharkia Governorate, Egypt. The associated pathogenic bacteria recovered from the isolated raw meat samples identified by microbiological, biochemical, and molecular methods is Bacillus. Clove extract was found to be the most effective and exhibited bacteriostatic and bactericidal activities against highly resistant strains of pathogenic bacteria. The plant extracts used in the study have great efficacy in reducing bacterial contamination and can be used as a safe alternative to antibiotics to avoid and control foodborne diseases. [ABSTRACT FROM AUTHOR]

IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.MethodsHere, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.ResultsIn standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).DiscussionThe results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis.

The development of antibiotic resistance compromises the effectiveness of our most effective defenses against bacterial infections, presenting a threat to global health. To date, a large number of research articles exist in the literature describing the case reports associated with extensively drug-resistant (XDR) and multidrug-resistant (MDR) bacterial strains. However, these findings are scattered, making it time-consuming for researchers to locate promising results and there remains a need for a comparative study to compile these case reports from various geographical regions including the Kingdom of Saudi Arabia. Additionally, no study has yet been published that compares the genetic variations and case reports of MDR and XDR strains identified from Saudi Arabia, the Middle East, Central Europe, and Asian countries. This study attempts to provide a comparative analysis of several MDR and XDR case reports from Saudi Arabia alongside other countries. Furthermore, the purpose of this work is to demonstrate the genetic variations in the genes underlying the resistance mechanisms seen in MDR and XDR bacterial strains that have been reported in Saudi Arabia and other countries. To cover the gap, this comprehensive review explores the complex trends in antibiotic resistance and the growing risk posed by superbugs. We provide context on the concerning spread of drug-resistant bacteria by analyzing the fundamental mechanisms of antibiotic resistance and looking into individual case reports. In this article, we compiled various cases and stories associated with XDR and MDR strains from Saudi Arabia and various other countries including China, Egypt, India, Poland, Pakistan, and Taiwan. This review will serve as basis for highlighting the growing threat of MDR, XDR bacterial strains in Saudi Arabia, and poses the urgent need for national action plans, stewardship programs, preventive measures, and novel antibiotics research in the Kingdom.

A significant obstacle to treating cancer is multidrug resistance (MDR), which is the capacity of cancerous cells to develop resistance to both traditional and cutting-edge chemotherapeutic treatments. Following the initial discovery that cellular pumps reliant on ATP were the root of chemotherapy resistance, more research has revealed the involvement of additional mechanisms, including increased drug metabolism, reduced drug entry, and compromised apoptotic pathways. Numerous projects have focused on MDR, and innumerable research has been conducted to better understand MDR and develop methods to mitigate its consequences. Multidrug resistance (MDR) is a key challenge in treating cancer. 90% of cancer-related fatalities are brought on by tumor metastasis and recurrence, which is possible with MDR. Drug resistance in cancerous cells is influenced by diverse internal and extrinsic variables, including genetic and epigenetic changes, drug efflux systems, DNA repair mechanisms, apoptosis, and autophagy. In this review paper, we list the potential hazards associated with cancer therapy in general, primarily multidrug resistance developing a theory for colorectal cancer in particular. We discussed the unique instance of multidrug resistance in colorectal cancer in malignancies generally and 5-fluorouracil, curcumin, and lipids as viable therapy options for the condition. The use of nanotechnology (mainly nanoparticles) has facilitated better in vitro as well as in vivo efficacy during preclinical phases, summarized below, allowing for a more thorough investigation of colorectal cancers and pancreatic carcinomas with their translation to following clinical trials.

Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram-negative drug-resistant bacterial pathogens. The lead compound SIMR 2404 had a minimal inhibitory concentration (MIC) of 2 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA). The MIC values against Gram-negative bacteria such as Escherichia coli and Actinobacteria baumannii were between 8-32 μg/mL. Time-kill experiments show that compound SIMR 2404 can rapidly kill tested bacteria. Compound SIMR 2404 was also found to rapidly kill MRSA persisters which display high levels of tolerance to conventional antibiotics. In antibiotic evolution experiments, MRSA quickly developed resistance to ciprofloxacin but failed to develop resistance to compound SIMR 2404 even after 24 serial passages. Compound SIMR 2404 was not toxic to normal human fibroblast at a concentration of 4 μg/mL which is twice the MIC concentration against MRSA. However, at a concentration of 8 μg/mL or higher, it showed cytotoxic activity indicating that it is not ideal as a candidate against Gram-negative bacteria. The acceptable toxicity profile and rapid antibacterial activity against MRSA highlight the potential of these molecules for further studies as anti-MRSA agents. [ABSTRACT FROM AUTHOR]

Bacterial infections continue to pose a significant global health challenge, with the emergence of multidrug-resistant (MDR) bacteria and biofilms further complicating treatment options. The rise of pan-resistant bacteria, coupled with the slow development of new antibiotics, highlights the urgent need for new therapeutic strategies. Nanotechnology-based biosensors offer fast, specific, sensitive, and selective methods for detecting and treating bacteria; hence, it is a promising approach for the diagnosis and treatment of MDR bacteria. Through mechanisms, such as destructive bacterial cell membranes, suppression of efflux pumps, and generation of reactive oxygen species, nanotechnology effectively combats bacterial resistance and biofilms. Nano-biosensors and related technology have demonstrated their importance in bacteria diagnosis and treatment, providing innovative ideas for MDR inhibition. This review focuses on multiple nanotechnology approaches in targeting MDR bacteria and eliminating antimicrobial biofilms, highlighting nano-biosensors via photodynamics-based biosensors, eletrochemistry biosensors, acoustic-dynamics sensors, and so on. Furthermore, the major challenges, opportunities of multi-physical-field biometrics-based biosensors, and relevant nanotechnology in MDR bacterial theranostics are also discussed. Overall, this review provides insights and scientific references to harness the comprehensive and diverse capabilities of nano-biosensors for precise bacteria theranostics and MDR inhibition. [ABSTRACT FROM AUTHOR]

The Australian roadside soil-derived fungus Penicillium shearii CMB-STF067 was prioritized for chemical investigation based on an SDA cultivation extract exhibiting both antibacterial properties and natural products with unprecedented molecular formulae (GNPS). Subsequent miniaturized 24-well plate cultivation profiling (MATRIX) identified red rice as optimal for the production of the target chemistry, with scaled-up cultivation, extraction and fractionation yielding four new xanthone–anthraquinone heterodimers, jugiones A–D (1–4), whose structures were assigned by detailed spectroscopic analysis and biosynthetic considerations. Of note, where 1–2 and 4 were active against the Gram-positive bacteria vancomycin-resistant Enterococcus faecalis (IC50 2.6–3.9 μM) and multiple-drug-resistant clinical isolates of Staphylococcus aureus (IC50 1.8–6.4 μM), and inactive against the Gram-negative bacteria Escherichia coli (IC50 > 30 μM), the closely related analog 3 exhibited no antibacterial properties (IC50 > 30 μM). Furthermore, where 1 was cytotoxic to human carcinoma (IC50 9.0–9.8 μM) and fungal (IC50 4.1 μM) cells, 2 and 4 displayed no such cytotoxicity (IC50 > 30 μM), revealing an informative structure activity relationship (SAR). We also extended the SAR study to other known compounds of this heterodimer class, which showed that the modification of ring G can reduce or eliminate the cytotoxicity while retaining the antibacterial activity. [ABSTRACT FROM AUTHOR]

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps’ overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

ABSTRACT: Objectives: A higher diversity of species, clones and genes have been increasingly implicated in carbapenemases spread, though the mobile genetic elements responsible for their acquisition and dispersion at local and global levels are less explored, particularly in species other than Klebsiella pneumoniae or Escherichia coli. We aim to explain the emergence of NDM-1 and KPC-3 carbapenemases in a Kluyvera cryocrescens isolate, and to shed light on the heterogeneity of genetic platforms and acquisition routes of blaNDM-1 in diverse Enterobacterales species in Portugal. Methods: A KPC-3 and NDM-1-producing K. cryocrescens colonizing a hospitalized patient in 2019 was characterized by whole-genome sequencing and antibiotic resistance profiling following standard methods. Conjugative transfer of carbapenemases genes was assessed by filter mating. Plasmids were reconstructed with in silico and in vitro approaches. blaNDM-1 genetic context was compared with that of diverse NDM-1-producing Enterobacterales species, previously described in Portugal. Results: K. cryocrescens K629 showed a multidrug resistance profile. Resistance gene blaKPC-3 was harboured by a Tn4401d transposon within a worldwide-spread IncN-ST15 plasmid (pKLU-KPC3), whereas blaNDM-1 was located in a Tn3000 within a non-typeable mosaic plasmid (pKLU-NDM1). The heterogeneous blaNDM-1 genetic platforms and variable plasmid backbones identified in various Enterobacterales species suggested multiple introductions of blaNDM-1 in Portugal, mediated by variable insertion sequences. Conclusions: We report the convergence of KPC-3 and NDM-1 in K. cryocrescens and the variable dissemination modes of these carbapenemases in different Enterobacterales species, underlining the need to track down genetic platforms responsible for carbapenemases diffusion.

Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin—a well-known hypoglycemic drug used in the treatment of type 2 diabetes—on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.

Background: Antimicrobial resistance (AMR) poses a global health threat, with lower-middle-income countries bearing a disproportionate burden. Surveillance of AMR under a One Health framework is needed to elucidate the associations among clinical, animal, and environmental AMR. This review aimed to describe the state of AMR in Ghana, focusing on One Health. Method: This review utilized the PRISMA guidelines and major databases to systematically search and analyze AMR in Ghana published from 1 January 2014 to 1 May 2023. Results: Out of the 48 articles that met the inclusion criteria, 28 studies were conducted on humans, 14 studies involved animals, and 6 studies focused on the environment. A total of 48 different pathogens were identified across the human, animal, and environmental sectors, with the most common being Escherichia coli (67%, n = 32), Klebsiella spp. (52%, n = 25), Pseudomonas spp. (40%, n = 19), and Salmonella spp. (38%, n = 18). Generally, a high prevalence of antibiotic resistance was observed among various bacterial species across the sectors. These bacteria exhibited resistance to commonly used antibiotics, with resistance to ampicillin and tetracycline exceeding 80%, and multidrug resistance (MDR) ranging from 17.6% in Shigella spp. to 100% in Acinetobacter spp. Conclusion: This review reaffirms the significant challenge of AMR in Ghana, with a high prevalence observed in the human, animal, and environmental sectors. Key pathogens (e.g., Staphylococcus aureus and Escherichia coli) found across the sectors emphasize the urgent need for a One Health approach to tackle AMR in Ghana.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood–brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.

Background: The development of multidrug resistance (MDR) is a major barrier to achieving effective chemotherapy in cancer. Studies have shown that epithelial ovarian cancer initially responds to platinum-based therapy, however, the recurrent type is often resistant to treatment and is associated with high mortality. Fucoxanthin, a natural component found in marine algae, possesses various pharmacologic properties. This study evaluated the cytotoxicity and resistance reversal activity of fucoxanthin on multidrug resistance-associated protein 2 (MRP2)- overexpressing, cisplatin-resistant ovarian cancer cells (A2780RCIS) and their parental cells (A2780). Methods: Cell viability was evaluated in the presence of different concentrations of fucoxanthin or cisplatin or fucoxanthin/cisplatin combination using the MTT assay. Propidium iodide staining and subG1 analysis were used to evaluate fucoxanthin potential for cell cycle modification and apoptosis induction in cancer cell lines. Results: The results showed that fucoxanthin was able to cause similar toxicity in both cell lines via apoptosis induction. Co-treatment of cells with cisplatin (3.125 to 100 µM) and nontoxic concentrations of fucoxanthin (1 and 2.5 µM) did not reverse resistance to cisplatin in A2780RCIS cells. Conclusion: Although fucoxanthin was not able to modify cisplatin resistance in ovarian cancer cells, it was equally effective in inducing apoptosis and death in both A2780 and A2780RCIS cells, indicating it is not an MRP2 substrate.

Abstract Background HMGB1 (high mobility group box B-1) exhibits crucial role in tumor genesis and development, including lung cancer. Whereas, more HMGB1-related details in non-small cell lung cancer (NSCLC) are still largely unclear. Methods The HMGB1 and inflammatory factors in malignant (MPE) and non-malignant pleural effusion (BPE) were determined by ELISA. Additionally, qRT-PCR, western blot, or immunohistochemistry were used to determine HMGB1, drug-resistant and apoptotic proteins’ expressions in NSCLC A549, A549-DDP cell lines, and xenograft model. Cell viability, migration/ invasion, and apoptosis were analyzed using MTT, Transwell, and flow cytometry assays, respectively. Results Inflammatory factors and HMGB1 expressions in MPE were significantly higher than BPE of NSCLC. Compared with preoperative and adjacent tissues, significantly higher HMGB1, drug-resistant protein, and anti-apoptotic protein expressions were observed in recurrent tissues. Overexpressed HMGB1 induced NSCLC cells to exhibit stronger aggressive, proliferative, and drug-resistant features. The related abilities were reversed when HMGB1 was interfered. Overexpressed HMGB1 showed a similar co-localization with drug resistant protein P-gp in cytoplasm in xenograft model, while low HMGB1 expression localized in cell nucleus. Conclusions HMGB1 overexpression significantly promoted the malignant progression and cisplatin resistance of NSCLC in vitro and in vivo.

Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram-negative drug-resistant bacterial pathogens. The lead compound SIMR 2404 had a minimal inhibitory concentration (MIC) of 2 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA). The MIC values against Gram-negative bacteria such as Escherichia coli and Actinobacteria baumannii were between 8–32 μg/mL. Time-kill experiments show that compound SIMR 2404 can rapidly kill tested bacteria. Compound SIMR 2404 was also found to rapidly kill MRSA persisters which display high levels of tolerance to conventional antibiotics. In antibiotic evolution experiments, MRSA quickly developed resistance to ciprofloxacin but failed to develop resistance to compound SIMR 2404 even after 24 serial passages. Compound SIMR 2404 was not toxic to normal human fibroblast at a concentration of 4 μg/mL which is twice the MIC concentration against MRSA. However, at a concentration of 8 μg/mL or higher, it showed cytotoxic activity indicating that it is not ideal as a candidate against Gram-negative bacteria. The acceptable toxicity profile and rapid antibacterial activity against MRSA highlight the potential of these molecules for further studies as anti-MRSA agents.

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case–control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). Conclusions: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. Trial Registration: Deutsches Register Klinischer Studien (https://www.drks.de/drks%5fweb/navigate.do?navigationId=trial.HTML&TRIAL%5fID=DRKS00023817), DRKS00023817, 2020–09-08. What is Known: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. What is New: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables. [ABSTRACT FROM AUTHOR]

Multidrug-resistant Gram-negative bacterial infections are exponentially increasing, posing one of the most urgent global healthcare and economic threats. Due to the lack of new therapies, the World Health Organization classified these bacterial species as priority pathogens in 2017, known as ESKAPE pathogens. This classification emphasizes the need for urgent research and development of novel targeted therapies. The majority of these priority pathogens are Gram-negative species, which possess a structurally dynamic cell envelope enabling them to resist multiple antibiotics, thereby leading to increased mortality rates. Despite 6 years having passed since the WHO classification, the progress in generating new treatment ideas has not been sufficient, and antimicrobial resistance continues to escalate, acting as a global ticking time bomb. Numerous efforts and strategies have been employed to combat the rising levels of antibiotic resistance by targeting specific resistance mechanisms. These mechanisms include antibiotic inactivating/modifying enzymes, outer membrane porin remodelling, enhanced efflux pump action, and alteration of antibiotic target sites. Some strategies have demonstrated clinical promise, such as the utilization of beta-lactamase inhibitors as antibiotic adjuvants, as well as recent advancements in machine-based learning employing artificial intelligence to facilitate the production of novel narrow-spectrum antibiotics. However, further research into an enhanced understanding of the precise mechanisms by which antibiotic resistance occurs, specifically tailored to each bacterial species, could pave the way for exploring narrow-spectrum targeted therapies. This review aims to introduce the key features of Gram-negative bacteria and their current treatment approaches, summarizing the major antibiotic resistance mechanisms with a focus on Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Additionally, potential directions for alternative therapies will be discussed, along with their relative modes of action, providing a future perspective and insight into the discipline of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Background: Meningitis can be attributed to bacterial, fungal, or viral agents. In this study, we demonstrate the common bacterial agents causing meningitis along with their antibiotics susceptibility pattern in patients of all age groups. Material and Methods: This retrospective, observational study was carried out in the Department of Microbiology with cerebrospinal fluid (CSF) samples collected from November 2019 to May 2022. We collected 1986 nonrepeat CSF samples from clinically suspected patients of bacterial meningitis, and clinical information about the patients was extracted from the hospital information system. Results: Out of the 1986 CSF samples included in our study, 150 (7.55%) were found to be positive on bacterial culture. Most of our patients were in the age group of 0-20 years. Common clinical manifestations observed in our patients were: high-grade fever, 87 patients (58%); severe headache, 126 patients (84%); neck rigidity, 47 patients (31.3%); altered mental status, 76 patients (50.7%) and photophobia, 83 patients (55.3%). The most commonly isolated bacteria was Acinetobacter species (30%). The mean length of hospitalization (37.76 ± 25.30), the mean total cell count, high levels of protein (mg/dl) and low levels of glucose (mg/dl) of CSF were statistically significant in meningitis caused by multidrug-resistant bacteria. Conclusion: We recognized the spectrum of pathogens causing meningitis at our center along with the antibiotic resistance pattern to guide and facilitate early treatment by primary health care professionals and family medicine practitioners. [ABSTRACT FROM AUTHOR]

There is a growing concern for exploring the animal-human interface through surveillance of peri-urban animals. Wildlife at this interface has been reported to pick up and redistribute antimicrobial-resistant bacteria and other infectious diseases. Samples from two stray Owl fledglings found at the National Veterinary Research Institute, Nigeria were used for this study. Corynebacterium amycolatum, Mammalicoccus siuri, and Escherichia coli were isolated and identified from cloacal and oropharyngeal swabs collected from the birds. Almost all (4/5) of the isolates had multidrug resistance. Also, three species of Leptospira (L. enterohaemorrhagica. L grippotyphosa, and L. mini) were identified by the microscopic agglutination technique (MAT). Our findings emphasised the growing One Health concerns for antimicrobial resistance (AMR) spread in the environment and the importance of Wildlife in periurban centres as sentinels for potential zoonotic transmission. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a global concern, posing risks to human and animal health. This research quantified antimicrobial resistance (AMR) in E. coli isolates from poultry fecal and environmental samples in Bangladesh and explored their association with antimicrobial use (AMU). We screened 725 fecal and 250 environmental samples from 94 conventional broilers and 51 Sonali farms for E. coli presence using MALDI-TOF mass spectrometry. AMU data were collected at flock levels, expressed as treatment incidence (TI), while minimum inhibitory concentrations (MIC) for 14 antibiotics were determined on five fecal E. coli isolates per farm and on all environmental isolates. MIC results were interpreted using human clinical breakpoints and EUCAST epidemiological cut-off values (ECOFFs). Acquired resistance against commonly used antimicrobial agents such as ciprofloxacin, tetracycline and ampicillin, was extremely high and predominantly clinically relevant. There was a moderate correlation between fecal and environmental antibiotic resistance index (ARI), but there was no significant correlation between AMU and AMR, suggesting that the observed AMR prevalence is unrelated to current AMU in poultry, but may be due to high historical AMU. A high level of multidrug resistance, including against critically important antimicrobials, was found in both farm types. Therefore, an AMR/AMU surveillance program is urgently needed in the poultry production sector of Bangladesh. [ABSTRACT FROM AUTHOR]

Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein–protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites.

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3–10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.

IntroductionPseudomonas aeruginosa infections are one of the leading causes of death in immunocompromised patients with cystic fibrosis, diabetes, and lung diseases such as pneumonia and bronchiectasis. Furthermore, P. aeruginosa is one of the main multidrug-resistant bacteria responsible for nosocomial infections worldwide, including the multidrug-resistant CCBH4851 strain isolated in Brazil.MethodsOne way to analyze their dynamic cellular behavior is through computational modeling of the gene regulatory network, which represents interactions between regulatory genes and their targets. For this purpose, Boolean models are important predictive tools to analyze these interactions. They are one of the most commonly used methods for studying complex dynamic behavior in biological systems.Results and discussionTherefore, this research consists of building a Boolean model of the gene regulatory network of P. aeruginosa CCBH4851 using data from RNA-seq experiments. Next, the basins of attraction are estimated, as these regions and the transitions between them can help identify the attractors, representing long-term behavior in the Boolean model. The essential genes of the basins were associated with the phenotypes of the bacteria for two conditions: biofilm formation and polymyxin B treatment. Overall, the Boolean model and the analysis method proposed in this work can identify promising control actions and indicate potential therapeutic targets, which can help pinpoint new drugs and intervention strategies.

ABSTRACT NorA, an extensively studied efflux pump in Staphylococcus aureus, has been connected to fluoroquinolone, antiseptic, and disinfection resistance. Several studies have also emphasized how efflux pumps, including NorA, function as the first line of defense of S. aureus against antibiotics. In this study, we have screened some chemically synthesized indole derivatives for their activity as efflux pump inhibitors (EPIs). The derivative SMJ-5 was found to be a potent NorA efflux pump inhibitor among the screened indole derivatives, owing to increased ethidium bromide and norfloxacin accumulation in norA over-expressing S. aureus. The combination of SMJ-5 and ciprofloxacin demonstrated the eradication of S. aureus biofilm and prolonged the post-antibiotic effect more than ciprofloxacin alone. SMJ-5 was able to inhibit staphyloxanthin virulence. In in vitro time-kill trials and in vivo efficacy investigations, the combination enhanced the bactericidal activity of ciprofloxacin against S. aureus. Additionally, reverse transcription PCR results revealed that SMJ-5 also inhibits the NorA efflux pump indirectly at the transcriptional level. IMPORTANCE The NorA efflux pump is the most effective resistance mechanism in S. aureus. The clinical importance of NorA efflux pumps is demonstrated by the expression of pump genes in S. aureus strains in response to fluoroquinolones and biocides. Along with the repercussions of decreased fluoroquinolone sensitivity, increasing expression of efflux pump genes by their substrate necessitates the importance of efflux pump inhibitors. Reserpine and verapamil are clinically used to treat ailments and have proven NorA inhibitors, but, unfortunately, the concentration needed for these drugs to inhibit the pump is not safe in clinical settings. In the current study, we have screened some indole derivatives, and among them, SMJ-5 was reported to potentiate norfloxacin and ciprofloxacin at their sub-inhibitory concentration by inhibiting the norA gene transcriptionally. Here we highlight the promising points of this study, which could serve as a model to design a therapeutic EPI candidate against norA over-expressing S. aureus.