Abstract:
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.
Authors: Tu MM, Carfrae LA, Rachwalski K, French S, Catacutan D, Gordzevich R, MacNair CR, Speagle ME, Werah F, Stokes JM, Brown ED.
Reference: Nat Microbiol. 2025 January 2; doi:10.1038/s41564-024-01883-8