Inosine monophosphate overcomes the coexisting resistance of mcr-1 and blaNDM-1 in Escherichia coli

Abstract

Introduction

The rise of antibiotic-resistant bacteria, particularly those harboring mcr-1 and bla_NDM-1, threatens public health by reducing the efficacy of colistin and carbapenems. Recently, the co-spread of mcr-1 and bla_NDM-1 has been reported, and the emergence of dual-resistant Enterobacteriaceae severely exacerbates antimicrobial resistance.

Objectives

This study aims to investigate the impact of mcr-1 and bla_NDM-1 expression on metabolism in Escherichia coli and to identify potential antimicrobial agents capable of overcoming the resistance conferred by these genes.

Methods

We employed non-targeted metabolomics to profile the metabolic perturbations of E. coli strains harboring mcr-1 and bla_NDM-1. The bactericidal effects of the differential metabolite, inosine monophosphate (IMP), were assessed both in vitro using time-killing assays and in vivo using a mouse infection model. The antimicrobial mechanism of IMP was elucidated through transcriptomic analysis and biochemical approaches.

Results

Metabolic profiling revealed significant alterations in the purine pathway, with IMP demonstrating potent bactericidal activity against E. coli strains carrying both resistance genes. IMP increased membrane permeability, disrupted proton motive force, reduced ATP levels, induced oxidative damage by promoting reactive oxygen species and inhibiting bacterial antioxidant defenses, and improved the survival rate of infected mice.

Conclusion

Our findings suggest that IMP could be a promising candidate for combating mcr-1 and bla_NDM-1-mediated resistance and provide a novel approach for discovering antimicrobial agents against colistin- and carbapenem-resistant bacteria.