SIGMA: Small molecule Inhibitors targeting the Genetic determinants of Mutagenesis and Adaptability in Mycobacterium tuberculosis

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To survive myriad chemical and host stresses, isogenic populations of pathogenic bacteria generate phenotypic variability by (i) developing transient subpopulations with distinct metabolic states, (ii) inducible metabolic remodelling, and (iii) stress-induced mutagenesis. Phenotypic variability fuels the ability of pathogenic bacteria to evolve antibiotic resistance, therefore next generation antibiotic therapies which manipulate phenotypic variability itself would be transformative. However, in clinically significant non-model pathogenic bacteria under infection-relevant conditions, we know little either about genetic determinants of phenotypic variability, or about how to modulate them with small molecules. Phenotypic variability in Mycobacterium tuberculosis causes the signature treatment challenges of tuberculosis, a disease which kills 1.4 million people annually. Therefore, we propose to systematically characterise the genetic determinants of phenotypic variability in M. tuberculosis as well as small molecules which modulate them in order to prototype next generation therapies. We will combine development of new methodology, mycobacteriology, functional genomics, and chemical biology in four aims: 1. to elucidate fine structure of metabolic subpopulations and identify genetic and small-molecule modulators of this fine structure. 2. to identify the comprehensive set of genes essential for metabolic remodelling to survive host-related stress conditions that do not permit growth. 3. to identify genetic and small-molecule modulators of inducible mutagenesis under infection-relevant stress. 4. to investigate three new modes of M. tuberculosis eradication to accelerate its killing, eliminate its antibiotic-tolerant subpopulations, and suppress evolution of resistance.