Kavanagh Madeline E, McLean Kirsty J, Gilbert Sophie H, Amadi Cecilia N, Snee Matthew, Tunnicliffe Richard B, Arora Kriti, Boshoff Helena I M, Fanourakis Alexander, Rebollo-Lopez Maria Jose, Ortega Fatima, Levy Colin W, Munro Andrew W, Leys David, Abell Chris, Coyne Anthony G
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
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.
J Med Chem. 2025 Jul 24;68(14):14416-14441. doi: 10.1021/acs.jmedchem.5c00478. Epub 2025 Jul 13.
Tuberculosis is the deadliest infectious disease in history and new drugs are urgently required to combat multidrug-resistant (MDR) strains of (). Here, we exploit the relience of on host-derived cholesterol to develop a novel class of antitubercular compounds that target 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 ( 40-160 nM), which potently inhibits enzyme activity in vitro ( < 100 nM), and the growth of in extracellular (MIC 0.4-1.5 μM) and intracellular assays (IC 1.7 μM). The structural data and lead compounds reported here will help study cholesterol metabolism and guide the development of novel antibiotics to combat MDR
结核病是历史上最致命的传染病，迫切需要新药来对抗多重耐药（MDR）结核分枝杆菌菌株。在此，我们利用结核分枝杆菌对宿主来源胆固醇的依赖性，开发了一类新型抗结核化合物，其靶向CYP125和CYP142；这两种酶催化胆固醇代谢的第一步。结合片段筛选和基于结构的药物设计来鉴定一种命中化合物，并指导双CYP125/142配体（40-160 nM）的合成优化，该配体在体外能有效抑制酶活性（<100 nM），并在细胞外（MIC 0.4-1.5 μM）和细胞内试验（IC 1.7 μM）中抑制结核分枝杆菌的生长。本文报道的结构数据和先导化合物将有助于研究结核分枝杆菌的胆固醇代谢，并指导开发对抗多重耐药结核分枝杆菌的新型抗生素
