Targeting Tuberculosis: Novel Scaffolds for Inhibiting Cytochrome bd Oxidase

Abstract Discovered in the 1920s, cytochrome bd is 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 for Mycobacterium tuberculosis ( Mtb ). Most previous drug discovery efforts towards cytochrome bd have involved analogs of the canonical substrate quinone, known as Aurachin D. Here we report six new cytochrome bd inhibitor scaffolds determined from a computational screen totaling over one million molecules and confirmed on target activity through in vitro testing. These scaffolds provide new avenues for lead optimization towards Mtb therapeutics.