DISEASE THEME: MYCOBACTERIAL PERSISTENCE

The TB pandemic

Tuberculosis (TB) causes more deaths annually than any other infectious disease and latently infects a third of the world’s population. A major barrier to the disease’s treatment is the capacity of its causative agent, Mycobacterium tuberculosis, to persist in host tissues. This contributes to the difficulty in clearing TB infections and the development of antibiotic resistance due to fractional killing. Improved treatment of TB depends on understanding and targeting the mechanisms that facilitate persistence.

To achieve this, we are studying the metabolic basis of mycobacterial persistence. We investigate the physiological roles and biochemical mechanisms of multiple redox enzymes implicated in persistence — first investigating these processes in the model organism M. smegmatis before translating findings into M. tuberculosis. The long-term goal is to validate novel targets for pharmaceutical development.

Current projects

1. Development of a cofactor biosynthesis pathway as an antituberculosis drug target (NHMRC New Investigator Grant, 2018 – 2021)
2. Carbon monoxide as a reserve energy source for carbon-limited mycobacteria (ARC DECRA Fellowship, 2017 – 2019)
3. Prediction and allevation of clinical nitroimidazole prodrug resistance (NHMRC Project Grant, 2018 – 2021, led by Prof Colin Jackson)
4. Physiological roles of DosR-regulated genes in mycobacterial redox and energy homeostasis (led by Prof Gregory Cook)
5. RISE: Revitalising Informal Settlements and their Environments (Wellcome Trust, 2018 – 2023)

Previous findings

We have shown that mycobacteria are more metabolically flexible than previously thought. This flexibility offers both opportunities and challenges for the development of metabolism as a target space for tuberculosis treatment (AMP 2014MSpectrum 2017).For example, we have revealed an unusual redox cofactor is critical for redox homeostasis and drug metabolism in mycobacteria (JMB 2015AEM 2016, Frontiers 2017) and are characterising its biosynthesis as a drug target (MMBR 2016ISME 2017a, Nature Comms 2019).

fermentation

Figure: Example of our work on mycobacterial persistence. Here we demonstrated that mycobacteria switch from respiratory to fermentative energy generation under hypoxic conditions. This process maintains redox homeostasis and enhances long-term survival (PNAS 2014b).

In other work, we are characterising the Dos regulon that allows mycobacteria to survive hypoxia. We have demonstrated that hypoxia survival requires metabolic adaptations such as fermentative hydrogen production (PNAS 2014b) and FAD sequestration (JBC 2019).

Research team

Staff: Dr Rhys Grinter (postdoctoral fellow), Thanavit Jirapanjawat (research assistant)
StudentsPaul Cordero (PhD), Katie Bayly (PhD), David Gillett (PhD)
Collaborators: Prof Gregory Cook, Prof Ross Coppel, Prof Colin Jackson, A/Prof Nick West