Fragment-Based Development of Small Molecule Inhibitors TargetingCholesterol 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 ofon host-derived cholesterol to develop a novel class of antitubercular compounds that targetCYP125 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 ofin extracellular (MIC0.4-1.5 &#x3bc;M) and intracellular assays (IC1.7 &#x3bc;M). The structural data and lead compounds reported here will help studycholesterol metabolism and guide the development of novel antibiotics to combat MDR