ANSTO User Meeting 2021

Cholesterol catabolism: An exploitable weakness in mycobacterial infections?

25 Nov 2021, 18:36

1m

Online

Poster Chemistry, Soft Matter & Crystallography Poster Session

Speaker

Mr Daniel Doherty (The University of Adelaide)

Description

Following the development of modern antibiotics and the net improvement of health care systems globally, tuberculosis (TB), a contagious and pathogenic bacterial infection caused by Mycobacterium tuberculosis, has been largely eliminated from developed countries. Despite this improvement TB remained a top 10 cause of death globally in 2020, which, when combined with the rise in multi-drug resistant tuberculosis (MDR-TB), represents an urgent global health concern. Other pathogenic mycobacteria including Mycobacterium ulcerans, the causative agent of Buruli Ulcer and Mycobacterium abscessus, a bacterium that affects cystic fibrosis patients, are also emerging public health threats. Mycobacteria are unique in their ability to metabolise host cell cholesterol, and this pathway has become a target for new antibiotic treatments to drug-resistant infections. The cytochrome P450 enzymes of the CYP125, CYP142 and CYP124 families initiate cholesterol metabolism. There are different numbers of cholesterol metabolising P450s in each Mycobacterium species. For example, Mycobacterium ulcerans and Mycobacterium tuberculosis have one of each CYP125, CYP142 and CYP124 enzymes, while Mycobacterium abscessus has four different CYP125 enzymes and no copies of CYP142 and CYP124. The reasons for different P450 profiles between mycobacteria remain unknown, as does a mechanistic understanding of the P450-mediated cholesterol oxidation. This project aims to understand the structural, evolutionary and mechanistic differences between enzymes of these three families. Also, screening of these enzymes as targets for a new class of cholesterol-based, anti-tubercular inhibitors will be undertaken.