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 for 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 A/Prof Colin Jackson)
4. Physiological roles of DosR-regulated genes in mycobacterial redox and energy homeostasis (led by Prof Gregory Cook)

Previous findings

We have shown that mycobacteria are more metabolically flexible than previously thought. For example, we have revealed an unusual redox cofactor is critical for redox homeostasis and drug metabolism in mycobacteria (JMB 2015AEM 2016MMBR 2016ISME 2017a). We have also shown that mycobacteria survive hypoxia by switching from respiration to fermentation (PNAS 2014b). This flexibility offers both opportunities and challenges for the development of metabolism as a target space for tuberculosis treatment (AMP 2014MSpectrum 2017).

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).

Research team

Staff: Blair Ney (Research Assistant)
StudentsPaul Cordero (PhD), Zahra Islam (PhD), Katie Bayly (Honours)
Co-supervised students: Liam Harold (PhD), Brendon Lee (PhD), Reuben Vercoe (PhD)
Collaborators: Prof Gregory Cook, A/Prof Colin Jackson, Dr Ghader Bashiri, Prof Ross Coppel

We will be advertised to recruit a postdoc to study redox and energy metabolism in Mycobacterium tuberculosis at the start of 2018. Please email chris.greening@monash.edu if you would like to make inquiries in advance.