Fragment-Based Development of Small Molecule Inhibitors Targeting Cholesterol Metabolism.

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