Exploiting the fitness cost of metallo-β-lactamase expression can overcome antibiotic resistance in bacterial pathogens

Nat Microbiol. 2025 Jan;10(1):53-65. doi: 10.1038/s41564-024-01883-8. Epub 2025 Jan 2.

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.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / pharmacology
  • Azithromycin* / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Carbapenems / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Multiple, Bacterial / genetics
  • Female
  • Genetic Fitness
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Zinc* / metabolism
  • Zinc* / pharmacology
  • beta-Lactamases* / genetics
  • beta-Lactamases* / metabolism

Substances

  • beta-Lactamases
  • Azithromycin
  • Anti-Bacterial Agents
  • Zinc
  • Carbapenems
  • Bacterial Proteins