AMB Express最新文献

This study evaluates the potential of repurposed non-antibiotic drugs as possible treatments for methicillin-resistant Staphylococcus aureus (MRSA) skin infection, through a comprehensive approach combining in silico, in vitro, and in vivo methodologies. From 198 protein targets previously identified through multi-omics analysis, 10 essential, druggable, broad-spectrum targets were selected. Three promising non-antibiotic ligands (rupatadine, orlistat, and citric acid) were evaluated through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), molecular docking, cytotoxicity testing, and a murine model of MRSA skin infection. Rupatadine, orlistat, and citric acid showed MICs of 0.031 mg/mL, 1.5 mg/mL, and 2.5 mg/mL, respectively. Rupatadine demonstrated the most potent anti-MRSA activity, with molecular docking revealing favorable binding energy (- 3.45 kcal/mol) to Aminoacyl transferase (FemA). Serial passage experiments over eight passages showed no resistance development against rupatadine in one MRSA strain and only twofold increase in another, compared to 8-13 fold increases observed with conventional antibiotics. Checkerboard assays revealed synergistic effects between rupatadine and β-lactam antibiotics (cefazolin and cefotaxime, FICI = 0.3). FemA is essential in cell wall biosynthesis and represents an essential target for anti-MRSA agents. Functional enrichment and pathway network analyses revealed significant disruption of biological processes governing peptidoglycan biosynthesis and cell wall biogenesis, which indicates the possibility of rupatadine compromising S. aureus cell wall integrity through interference with peptidoglycan assembly pathways, supporting its potential as a repurposed anti-MRSA agent. Rupatadine showed favorable tolerance on human skin fibroblast cells (IC₅₀: 1150 µg/mL), and significantly reduced bacterial count in a murine model.

Antibiotic misuse has triggered a global health crisis due to the rise of antimicrobial-resistant microorganisms. Recent studies suggest that nanoparticles (NPs), particularly silver nanoparticles, may provide a solution. However, their toxicity necessitates the development of novel carriers to enhance targeting while minimizing cytotoxicity. This study aimed to synthesize, characterize mesoporous silica nanoparticles (MSN) incorporated with silver alone or combined with zinc, and evaluate their antibacterial, antibiofilm, and cytotoxic properties. Characterization through X-ray diffraction (XRD) and scanning electron microscopy (SEM), revealed particle sizes between 413 and 560 nm. Antibacterial activity was assessed via the broth-dilution method against Staphylococcus aureus ATCC 25,923, Escherichia coli ATCC 25,922, Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33,591, and five multidrug-resistant pathogens (MDR). Two types of silver-incorporated mesoporous silica nanoparticles were synthesized: Ag/MCM-48 (10 mmol Ag) and Ag/Zn/MCM-48 (10 mmol Ag + 10 mmol Zn). The minimum inhibitory and minimum bactericidal concentrations ranged from 7.8 to 31.25 and 7.8 to 62.5 µg/mL, respectively. Ag/MCM-48 NPs exhibited 78% antibiofilm activity against MRSA ATCC 33,591, while Ag/Zn/MCM-48 NPs displayed up to 90% antibiofilm activity against MDR bacteria. Cytotoxicity assays revealed promising results, with CC₅₀ values of 169.16 ± 6.43 µg/mL and 19.95 ± 0.63 µg/mL for Ag/Zn/MCM-48 NPs and Ag/MCM-48 NPs against Vero cell line, respectively. The IC₅₀ values of Ag/Zn/MCM-48 and Ag/MCM-48 NPs were 62.17 ± 2.15 µg/mL and 3.58 ± 0.12 µg/mL against Caco-2 cell line, respectively. Accordingly, our synthesized silver/zinc incorporated mesoporous silica NPs present a safer antibacterial and antibiofilm agent with lower cytotoxicity than silver NPs, making them a promising alternative for combating MDR bacteria.

Burkholderia is a significant pathogen that causes disease burden across the globe. In particular, Burkholderia cenocepacia and Burkholderia multivorans are the predominant isolates that infect people with cystic fibrosis (CF) and cause hospital-acquired infections. Understanding antimicrobial resistance and virulent factors among these species is of great significance for addressing this growing resistance burden. Initially, we retrieved 75 complete genome sequences of B. cenocepacia and B. multivorans from NCBI database and analysed them for antimicrobial resistance (AMR) and virulent factors. This yielded 368 antimicrobial resistance genes and 202 virulent factors after removing the duplicates. Further, a comprehensive interaction network was constructed using STRING, which was visualized and analysed using Cytoscape. Through cytoHubba and MCODE analysis, eight key hub genes FliF, FliG, FliM, FliS, FlgB, FlgC, FlgD and FlgK were identified. Additionally, a non-homology analysis was conducted to ensure that the key nodes do not exhibit similarity with the human genome and gut microbiota. Functional enrichment analysis revealed their significant role in the flagellar assembly pathway, particularly in bacterial motility, colonization and biofilm formation. Notably, seven hub genes were enriched in bacterial-type flagellum-dependent cell motility pathway and cellular localization. It is worth noting that 17,967 phytochemicals were exploited to identify the potent hit compounds against each of the identified hub genes. Interestingly, the hit molecules were found to form several key interactions with the targets, indicating their potential as promising therapeutic agents for combating AMR. Overall, the identified hub genes and their potent inhibitors present compelling targets for novel antimicrobial therapies in CF, underscoring the need for future experimental validation.

Neurosyphilis (NS) is a chronic central nervous system infection caused by Treponema pallidum. Owing to its diverse clinical manifestations and the limited sensitivity of current diagnostic methods, NS is difficult to diagnose. Understanding the molecular mechanisms of NS and identifying reliable biomarkers are essential for improving diagnostic and therapeutic strategies. This study employed Mendelian randomization (MR) analysis to explore the causal relationships among protein ratio quantitative trait loci (rQTLs), cerebrospinal fluid (CSF) metabolites, and syphilis risk at various stages. The results revealed that several rQTLs, including CD46/TNFRSF14 and TBC1D23/TBC1D5, were closely associated with syphilis risk, whereas others, such as BANK1/HEXIM1 and GOPC/HEXIM1, exhibited protective effects. Mediation analysis further identified key CSF metabolites, such as N-acetyltaurine and bilirubin, as important mediators linking rQTLs and syphilis progression. Through integrated analysis of cis-proteins from rQTLs and transcriptomic data from CD4 + T-cells of NS patients, METAP2 was identified as a key biomarker in NS, with the potential mechanisms elucidated. Importantly, T. pallidum may inhibit CD4 + T-cell proliferation by modulating METAP2, thereby accelerating disease progression. These findings offer new insights into the pathogenesis of NS and highlight METAP2 as a potential biomarker, laying a foundation for improving diagnostic and therapeutic strategies.