Fragment-Based Development of Small Molecule Inhibitors Targeting Mycobacterium tuberculosis Cholesterol Metabolism.
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American Chemical Society (ACS)
https://doi.org/10.1021/acs.jmedchem.5c00478
https://doi.org/10.1021/acs.jmedchem.5c00478
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Publication status: Published
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.
M.E.K. was supported by a Commonwealth (University of Cambridge) Scholarship awarded in conjunction with the Cambridge Commonwealth Trust and Cambridge Overseas Trust. A.G.C. and K.J.M. were supported by grants from the BBSRC (grant no. BB/I019669/1 and BB/I019227/1) and M.S. was supported by BBSRC (grant no. BB/M011208/1). This work was funded in part by the Division of Intramural Research of the NIAID/NIH and we acknowledge the Diamond Light Source and the staff of the beamlines i02, i04, and i24 (proposal mx8997, mx17773, and mx24447) for assistance that contributed to the results presented here.
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.
M.E.K. was supported by a Commonwealth (University of Cambridge) Scholarship awarded in conjunction with the Cambridge Commonwealth Trust and Cambridge Overseas Trust. A.G.C. and K.J.M. were supported by grants from the BBSRC (grant no. BB/I019669/1 and BB/I019227/1) and M.S. was supported by BBSRC (grant no. BB/M011208/1). This work was funded in part by the Division of Intramural Research of the NIAID/NIH and we acknowledge the Diamond Light Source and the staff of the beamlines i02, i04, and i24 (proposal mx8997, mx17773, and mx24447) for assistance that contributed to the results presented here.