Targeting Tuberculosis: Novel Scaffolds for Inhibiting Cytochrome bd Oxidase

Abstract

AbstractDiscovered in the 1920s, cytochromebdis a terminal oxidase that has received renewed attention as a drug target since its atomic structure was first solved in 2016. Only found in prokaryotes, we study it here as a drug target forMycobacterium tuberculosis(Mtb). Most previous drug discovery efforts towards cytochromebdhave involved analogs of the canonical substrate quinone, known as Aurachin D. Here we report six new cytochromebdinhibitor scaffolds determined from a computational screen totaling over one million molecules and confirmed on target activity throughin vitrotesting. These scaffolds provide new avenues for lead optimization towardsMtbtherapeutics.