Lay summary
Antimicrobial resistance is a global health crisis. Drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, are extremely difficult to treat, with long treatment regimens (9-20 months) and low cure rates (2-50%). Antibiotic killing is intrinsically linked to bacterial metabolism, while antibiotic resistance in M. tuberculosis is predominantly a result of mutations in antibiotic targets or pro-drug activators that have crucial roles in metabolism, DNA replication, transcription and translation. Here, we hypothesise that primary drug resistance dysregulates mycobacterial metabolism and (I) increases susceptibility to killing by and (II) restricts the evolution of drug resistance against antibiotics that are able to exploit this dysregulation. Using a combination of microbiological, metabolomic and in vivo studies, we will reveal and then exploit these metabolic perturbations in drug-resistant strains to identify an entirely new suite of treatment strategies that increase antibiotic efficacy, reduce treatment times and prevent the emergence of drug resistance.