Tu Megan M, Carfrae Lindsey A, Rachwalski Kenneth, French Shawn, Catacutan Denise, Gordzevich Rodion, MacNair Craig R, Speagle Melissa E, Werah Firas, Stokes Jonathan M, Brown Eric D
Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Nat Microbiol. 2025 Jan;10(1):53-65. doi: 10.1038/s41564-024-01883-8. Epub 2025 Jan 2.
Carbapenems are last-resort antibiotics for treating bacterial infections. The widespread acquisition of metallo-β-lactamases, such as VIM-2, contributes to the emergence of carbapenem-resistant pathogens, and currently, no metallo-β-lactamase inhibitors are available in the clinic. Here we show that bacteria expressing VIM-2 have impaired growth in zinc-deprived environments, including human serum and murine infection models. Using transcriptomic, genomic and chemical probes, we identified molecular pathways critical for VIM-2 expression under zinc limitation. In particular, disruption of envelope stress response pathways reduced the growth of VIM-2-expressing bacteria in vitro and in vivo. Furthermore, we showed that VIM-2 expression disrupts the integrity of the outer membrane, rendering VIM-2-expressing bacteria more susceptible to azithromycin. Using a systemic murine infection model, we showed azithromycin's therapeutic potential against VIM-2-expressing pathogens. In all, our findings provide a framework to exploit the fitness trade-offs of resistance, potentially accelerating the discovery of additional treatments for infections caused by multidrug-resistant bacteria.
碳青霉烯类是治疗细菌感染的最后一道抗生素防线。广泛获得金属β-内酰胺酶，如VIM-2，导致了耐碳青霉烯病原体的出现，目前临床上尚无金属β-内酰胺酶抑制剂。在此，我们表明，表达VIM-2的细菌在锌缺乏的环境中生长受损，包括人血清和小鼠感染模型。通过转录组学、基因组学和化学探针，我们确定了锌限制条件下对VIM-2表达至关重要的分子途径。特别是，包膜应激反应途径的破坏降低了表达VIM-2的细菌在体外和体内的生长。此外，我们表明VIM-2的表达破坏了外膜的完整性，使表达VIM-2的细菌对阿奇霉素更敏感。使用系统性小鼠感染模型，我们展示了阿奇霉素对表达VIM-2病原体的治疗潜力。总之，我们的发现提供了一个框架，以利用耐药性的适应性权衡，可能加速发现针对多重耐药细菌引起的感染的其他治疗方法。
