Samsher Singh, Pearly Shuyi Ng, Umayal Lakshmanan, Vikneswaran Mathiyazakan, Thomas J. Wiggins, Bei Shi Lee, Shi Hua Ang, Sandra Wei Lin Sim, May Delos Santos, Garrett C. Moraski, Marvin Miller, Michael Berney, Gerhard Grüber, Kévin Pethe
High Resolution Image Download MS PowerPoint Slide The Mycobacterium tuberculosis cytochrome bcc:aa 3 (cyt- bcc:aa 3 ) oxidase is a validated drug target for tuberculosis treatment. In addition to telacebec (Q203), a clinical-stage drug candidate, several preclinical cyt- bcc: aa 3 inhibitors have been reported. However, the bactericidal potency of cyt- bcc: aa 3 inhibitors is limited by cytochrome bd oxidase (cyt- bd ), an alternative terminal oxidase. We developed a high-throughput whole-mycobacteria assay to identify new cyt- bd inhibitors. Screening 115,398 small molecules identified several new chemical series, including a pyrazolo-quinazoline amine series. Chemical optimization yielded the potent derivative ETX1975-3, which, in combination with Q203, is bactericidal against M. tuberculosis, retains activity against a panel of M/XDR M. tuberculosis clinical isolates, and also shows efficacy against nontuberculous mycobacteria (NTM). Mode of action studies validated the cyt- bd target as the molecular target. While further chemical optimization is required, favorable microbiological, ADMET, and in vivo potency of ETX1975-3 makes it a promising preclinical candidate for tuberculosis and NTM infections.