Transition metal homoeostasis is key to metabolism and drug tolerance of Mycobacterium abscessus

Abstract

Abstract Antimicrobial resistance (AMR) is one of the major challenges humans are facing this century. Understanding the mechanisms behind the rise of AMR is therefore crucial to tackling this global threat. The presence of transition metals is one of the growth-limiting factors for both environmental and pathogenic bacteria, and the mechanisms that bacteria use to adapt to and survive under transition metal toxicity resemble those correlated with the rise of AMR. A deeper understanding of transition metal toxicity and its potential as an antimicrobial agent will expand our knowledge of AMR and assist the development of therapeutic strategies. In this study, we investigate the antimicrobial effect of two transition metal ions, namely cobalt (Co2+) and nickel (Ni2+), on the non-tuberculous environmental mycobacterium and the opportunistic human pathogen Mycobacterium abscessus. The minimum inhibitory concentrations of Co2+ and Ni2+ on M. abscessus were first quantified and their impact on the bacterial intracellular metallome was investigated. A multi-omics strategy that combines transcriptomics, bioenergetics, metabolomics, and phenotypic assays was designed to further investigate the mechanisms behind the effects of transition metals. We show that transition metals induced growth defect and changes in transcriptome and carbon metabolism in M. abscessus, while the induction of the glyoxylate shunt and the WhiB7 regulon in response to metal stresses could be the key response that led to higher AMR levels. Meanwhile, transition metal treatment alters the bacterial response to clinically relevant antibiotics and enhances the uptake of clarithromycin into bacterial cells, leading to increased efficacy. This work provides insights into the tolerance mechanisms of M. abscessus to transition metal toxicity and demonstrates the possibility of using transition metals to adjuvant the efficacy of currently using antimicrobials against M. abscessus infections.