What doesn't kill tuberculosis makes it stronger: carbon monoxide as a host-derived energy source for mycobacterial persistence

Tuberculosis (TB) is now the leading cause of death from infectious disease worldwide. The causative agent evades host defences and drug treatments by living in a persistent state within host macrophages. To do so, it must stay energised despite host-imposed nutrient and oxygen limitation. I propose here an unprecedented strategy for how M. tuberculosis achieves this: using host-derived carbon monoxide (CO) as an energy source. Whereas CO is lethal to most pathogens, M. tuberculosis is highly tolerant of the gas and encodes the enzyme to respire it.

This research program will determine how and why CO influences M. tuberculosis growth, survival, and infection. This will be achieved through four major projects. The first will systematically investigate how different concentrations of CO affect the physiology of the organism. Projects 2 and 3 will understand how M. tuberculosis both tolerates CO and respires the gas; to do, I will integrate findings from biochemical studies of purified enzymes with physiological characterisation of M. tuberculosis strains in pure culture, infected macrophages, and an animal model. The fourth project will gain insights into these processes in clinical strains.

I am ideally suited to deliver on this ambitious but feasible research program. Five years post-PhD, I lead an excellently-resourced 16-person microbiology and biochemistry laboratory within the supportive research environment of Monash University. The outlined program builds on compelling preliminary data and my discovery, published in four first-author articles in PNAS and Nature, that trace gases serve as hidden energy sources supporting bacterial persistence. I will use my proven existing expertise in mycobacterial genetics, physiology, and biochemistry, while developing capacity in the area of host-microbe interactions.

These findings will transform understanding of how M. tuberculosis persists in host tissues, and may justify and guide targeted drug development.