International Journal of Antimicrobial Agents最新文献

Multidrug-resistant (MDR) Gram-negative bacteria, particularly Klebsiella pneumoniae, represent a significant threat to global health. Given the shortage of new antibiotics, bacteriophages (phages) offer a promising alternative. Understanding bacteria-phage interactions and resistance mechanisms is vital for optimising phage therapy. We aimed to investigate the resistance mechanism of an MDR clinical isolate, K. pneumoniae UCSD1 (designated as KpUCSD1) against a newly isolated phage ΦKpUCSD1. A phage-resistant mutant KpUCSD1R was collected at 24 h following treatment of KpUCSD1 with ΦKpUCSD1. Comparative genomic analysis identified mutations in KpUCSD1R, and complementation was conducted to evaluate the impact of these genes towards phage resistance. Spot tests and time-kill kinetics were performed to evaluate the bacterial susceptibility to ΦKpUCSD1. The role of galE in phage infection was evaluated with adsorption and lipopolysaccharide (LPS) assays. Mutations were identified in ubiH and galE of KpUCSD1R, and galE was crucial for phage infection, as complementing KpUCSD1R with wild-type galE restored its susceptibility to ΦKpUCSD1. The clean knockout strain, KpUCSD1ΔgalE exhibited complete loss of phage susceptibility owing to defective phage adsorption. Further analyses revealed that mutated and loss of galE resulted in truncated LPS. Interestingly, phage resistance imposed a fitness trade-off associated with galE disruption, resulting in collateral antibiotic effects, namely increased susceptibility to aminoglycosides, chloramphenicol and polymyxin, alongside reduced susceptibility to tetracycline and meropenem. This study demonstrates for the first time that galE mutation in K. pneumoniae diminishes phage adsorption by causing truncation of the LPS. The trade-off leads to increased susceptibility to several antibiotics, offering a potential therapeutic advantage in treating MDR infections.

Background: Quinolone-resistant Shigella has emerged as a significant global public health challenge.

Methods: We assembled a global collection of 8325 plasmid-mediated quinolone resistance (PMQR)-positive Shigella isolates (1998-2025) and subjected them to comprehensive genomic analysis.

Results: Geographically, the isolates spanned 37 countries, with the majority sourced from the United States (47.02%) and United Kingdom (32.28%). Eight distinct PMQR genes-aac(6')-Ib-cr, oqxAB, qepA, qnrA, qnrB, qnrD, qnrS, and qnrVC-were identified in the Shigella analyzed. qnrS was the most predominant PMQR gene (62.05%), followed by qnrB (38.76%). One hundred and eight sequence types (STs) were identified among the PMQR-positive Shigella isolates, with ST152 predominating (59.51%). Notably, multiple antibiotic resistance genes (ARGs) were universal in PMQR-positive Shigella, with aph(6)-Id (5825/8325), tet(B) (2398/8325), and blaTEM-1 (2232/8325) most prevalent. PMQR-positive Shigella from developed countries displayed a significant decreasing trend in ARGs abundance as collection year and the opposite trend in the abundance of virulence factors (VFs) between developed and developing countries (P < 0.001). Correlation analysis demonstrated the mobile genetic elements constitute principal vectors for PMQR genes spread. Plasmid replicons abundance positively correlated with ARGs abundance (P < 0.001), demonstrating plasmid-driven ARGs spread in PMQR-positive Shigella. In addition, high genetic similarity among geographically dispersed PMQR-positive Shigella isolates implies intercountry dissemination.

Conclusions: These findings elucidate PMQR-positive Shigella genomic characteristics and transmission dynamics, necessitating global surveillance reinforcement against this antimicrobial resistance threat.

The increasing prevalence of antibiotic-resistant Salmonella Typhimurium has highlighted the urgent need for alternative therapeutic strategies. This study evaluated the antibacterial efficacy of a genetically engineered bacteriophage displaying the antimicrobial peptide, LL37, against S. Typhimurium. Despite displaying LL-37 in the virion structure, the engineered-phage exhibited thermal and pH stabilities comparable to those of the wild-type phage. Notably, it demonstrated enhanced antibacterial activity, primarily owing to an increased adsorption rate. In a cell lysis assay, the engineered-phage sustained bacterial suppression for 24-72 h, whereas the wild-type phage allowed bacterial regrowth, owing to the emergence of phage-resistant mutants. In epithelial cell interaction assays, the engineered-phage significantly reduced bacterial attachment and internalization compared with its wild-type counterpart. Furthermore, intracellular survival assays revealed that the engineered-phage effectively reduced bacterial persistence in host cells. In an in vivo prophylactic assay, the engineered-phage significantly improved larval survival in a Galleria mellonella infection model in a dose-dependent manner, providing protection equivalent to 100 times that of the wild-type phage. Notably, no significant cytotoxicity was observed at either the cellular or animal levels, supporting the safety and therapeutic potential of the engineered-phage. These findings highlight phage engineering as a promising strategy for enhancing antibacterial efficacy and combating antibiotic-resistant bacterial infections.