Abstract
Mycobacterium tuberculosis (MTB) is one of the leading causes of death worldwide and the rise in multidrug-resistant (MDR)- and extensively drug-resistant (XDR)-TB highlights an urgent global requirement for novel therapeutic strategies. Antibiotic killing is intrinsically linked to bacterial metabolism and redox homeostasis; however, drug-resistance in M. tuberculosis is often driven by mutations in genes that regulate these pathways. Here, I hypothesize that antibiotic resistance dysregulates mycobacterial metabolism or redox homeostasis and renders them hypersensitive to killing by drugs that can exploit this dysregulation. The aim of this study was to identify biological pathways that when inhibited lead to enhanced killing of drug-resistant redox-detoxification mutants of M. tuberculosis (i.e. isoniazid (INH)-resistant katG catalase mutant and an ethionamide (ETH)-resistant mshA antioxidant mutant). The inactivation of katG catalase or mshA mycothiol biosynthesis rendered drug-resistant strains of MTB hypersensitive to killing by a wide variety of antibiotics that target a range of biological pathways. Furthermore, the increased killing was often unique, with the katG catalase being hypersensitive to drugs that had no increased lethality against the mshA mutant and vice versa. For example, the normally bacteriostatic drug, Q203 that targets the cytochrome bc1 respiratory complex, was bactericidal against the katG inactivation in the INH-1 resistant mutant. Further to this, CRISPR interference was used to construct a broader set of metabolically-compromised strains, with Q203 identified as also having a bactericidal phenotype against sodA and cydB depletion strains. Collectively, these results have demonstrated the importance of redox-detoxification systems for the ability of M. tuberculosis to mitigate antibiotic efficacy. More importantly, these results contribute to the overarching goal of developing more effective treatment regimens to reduce the global burden of tuberculosis (TB).