Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB), remains a leading cause of infectious disease mortality and morbidity. Globally there are significant discrepancies in TB prevalence, with indigenous populations and low socioeconomic communities bearing the largest TB burdens.

Whilst TB is a curable disease, drug-resistant strains of M. tuberculosis have limited treatment options and threaten to make one of the world’s deadliest pathogens completely incurable. By understanding the mechanisms and biological costs of drug-resistance, our work seeks to identify novel therapies that can reduce treatment times, prevent the emergence of resistance and ultimately improve clinical outcomes.

Here I will present our work that uses high-throughput genetic essentiality screens, mycobacterial genetics and antimicrobial susceptibility assays to  describe how drug-resistance imposes a physiological cost, (ii) how this physiological cost can be therapeutically exploited and (iii) how low level resistance phenotypes accelerate the evolution of high-level potentially untreatable drug resistant strains.