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Dysregulating metabolism to eradicate drug-resistant Mycobacterium tuberculosis

48 months
Approved budget:
Dr Matthew McNeil
Professor Gregory Cook
Professor Rhea Coler
Dr Adrian Jinich
Dr Veronica Playle
Health issue:
Infectious disease
Proposal type:
Sir Charles Hercus Fellowship
Lay summary
Antimicrobial resistance is a major international public health crisis. Central to this problem are drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis. Drug-resistant strains of M. tuberculosis are becoming increasingly difficult to treat, with cure rates as low as 2%. Drug resistance in M. tuberculosis is driven exclusively through chromosomal mutations that typically occur in antibiotic targets or pro-drug activators that play crucial roles in core cellular processes. I hypothesize that mutations in core cellular processes have downstream impacts that ultimately dysregulate cellular metabolism in drug-resistant strains of M. tuberculosis. Here, using a combination of microbiological, molecular, metabolomic and next-generation sequencing approaches, I will characterise and exploit this metabolic dysregulation to develop an entirely new suite of treatment options that rapidly eliminate and prevent the emergence of drug resistance in M. tuberculosis.