Active Infection & Immunity Genetics & Molecular Biology

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

Funder UKRI
Recipient organisation The Francis Crick Institute
Funding £1.3M
Period Jan 2023 — Dec 2027

In plain English

AI plain-English summary

Tuberculosis kills 1.4 million people each year, and the bacterium that causes it, *Mycobacterium tuberculosis*, is a master of disguise—it can switch between different metabolic states, remodel itself to survive stress, and even ramp up its own mutation rate to dodge antibiotics. This project aims to systematically identify the genes that control these shape-shifting abilities and find small molecules that can block them. Current antibiotics kill actively growing bacteria but often miss the dormant, drug-tolerant subpopulations that fuel relapse and resistance. The researchers will map the genetic determinants of three key forms of bacterial adaptability—metabolic subpopulations, stress-induced remodelling, and inducible mutagenesis—under conditions that mimic human infection. They will then screen for small molecules that can shut these processes down. If successful, this work could prototype a fundamentally new class of tuberculosis therapies: drugs that do not just kill bacteria directly but instead strip them of their ability to adapt, making them vulnerable to existing antibiotics and the immune system. The project also tests three novel eradication strategies designed to accelerate killing, eliminate tolerant subpopulations, and suppress the evolution of resistance. Because much of this is fundamental science—mapping unknown genetic circuits in a non-model pathogen—the immediate clinical payoff is uncertain, but understanding how bacteria control their own variability could open entirely new avenues for anti-evolution drugs.

View original technical description
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.

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Researchers

Eachan Johnson (Principal Investigator)

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Original classification

Research Grant

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