2. Academic Validation
  3. Fragment-Based Development of Small Molecule Inhibitors Targeting Mycobacterium tuberculosis Cholesterol Metabolism

Fragment-Based Development of Small Molecule Inhibitors Targeting Mycobacterium tuberculosis Cholesterol Metabolism

  • J Med Chem. 2025 Jul 24;68(14):14416-14441. doi: 10.1021/acs.jmedchem.5c00478.
Madeline E Kavanagh 1,  Kirsty J McLean 2,  Sophie H Gilbert 1,  Cecilia N Amadi 2,  Matthew Snee 2,  Richard B Tunnicliffe 2,  Kriti Arora 3,  Helena I M Boshoff 3,  Alexander Fanourakis 1,  Maria Jose Rebollo-Lopez 4,  Fatima Ortega 4,  Colin W Levy 5,  Andrew W Munro 2,  David Leys 6,  Chris Abell 1,  Anthony G Coyne 1
Affiliations

Affiliations

  • 1 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • 2 Centre for Synthetic Biology of Fine and Specialty Chemicals (SYNBIOCHEM), Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
  • 3 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 4 Global Health R&D, GSK, Severo Ochoa 2, Tres Cantos 28760, Spain.
  • 5 Manchester Protein Structure Facility (MPSF), Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, U.K.
  • 6 Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
PMID: 40653654 DOI: 10.1021/acs.jmedchem.5c00478
Abstract

Tuberculosis is the deadliest infectious disease in history and new drugs are urgently required to combat multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Here, we exploit the relience of Mtb on host-derived Cholesterol to develop a novel class of antitubercular compounds that target Mtb 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 5m (KD 40-160 nM), which potently inhibits enzyme activity in vitro (KI < 100 nM), and the growth of Mtb in extracellular (MIC99 0.4-1.5 μM) and intracellular assays (IC50 1.7 μM). The structural data and lead compounds reported here will help study Mtb Cholesterol metabolism and guide the development of novel Antibiotics to combat MDR Mtb.

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