Fragment-Based Development of Small Molecule Inhibitors Targeting <i>Mycobacterium tuberculosis</i> Cholesterol Metabolism
Tuberculosis is the deadliest infectious disease in history and new drugs are urgently required to combat multidrug-resistant (MDR) strains of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Here, we exploit the relience of <i>Mtb</i> on host-derived cholesterol to develop a novel class of antitubercular compounds that target <i>Mtb</i> CYP125 and CYP142; the enzymes that catalyze the first step of cholesterol metabolism. A combination of fragment screening and structure-based drug design was used to identify a hit compound and guide synthetic optimization of a dual CYP125/142 ligand <b>5m</b> (<i>K</i><sub>D</sub> 40-160 nM), which potently inhibits enzyme activity in vitro (<i>K</i><sub>I</sub> < 100 nM), and the growth of <i>Mtb</i> in extracellular (MIC<sub>99</sub> 0.4-1.5 μM) and intracellular assays (IC<sub>50</sub> 1.7 μM). The structural data and lead compounds reported here will help study <i>Mtb</i> cholesterol metabolism and guide the development of novel antibiotics to combat MDR <i>Mtb.</i>
Authors
- Chris Abell (ORCID: https://orcid.org/0000-0001-9174-1987)
- David Leys (ORCID: https://orcid.org/0000-0003-4845-8443)
- Kirsty J. McLean (ORCID: https://orcid.org/0000-0002-7193-5044)
- M. Snee (ORCID: https://orcid.org/0000-0003-3138-4994)
- Fátima Ortega
- Madeline E. Kavanagh (ORCID: https://orcid.org/0000-0002-4735-1559)
- Anthony G. Coyne (ORCID: https://orcid.org/0000-0003-0205-5630)
- Helena I. Boshoff (ORCID: https://orcid.org/0000-0002-4333-206X)
- Kriti Arora (ORCID: https://orcid.org/0000-0002-4373-0367)
- Sophie H. Gilbert (ORCID: https://orcid.org/0000-0002-2760-9890)
- Andrew W. Munro (ORCID: https://orcid.org/0000-0002-4642-180X)
- Colin Levy (ORCID: https://orcid.org/0000-0002-9724-310X)
- Richard B. Tunnicliffe (ORCID: https://orcid.org/0000-0003-0499-4113)
- María José Rebollo-López
- Cecilia Nwadiuto Obasi (ORCID: https://orcid.org/0000-0002-2724-4262)
- Alexander Fanourakis
Institutions
- National Institutes of Health (US)
- University of Cambridge (GB)
- University of Manchester (GB)
- GlaxoSmithKline (France) (FR)
- Protein Technologies (United Kingdom) (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00478
- Citations
- 2
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Diamond Light Source
- Commonwealth Scholarship Commission
- Cambridge Overseas Trust
- Cambridge Commonwealth Trust
- Biotechnology and Biological Sciences Research Council