Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

Michael B. Harbut, Baiyuan Yang, Renhe Liu, Takahiro Yano, Catherine Vilchèze, Bo Cheng, Jonathan Lockner, Hui Guo, Chenguang Yu, Scott G. Franzblau, H. Mike Petrassi, William R. Jacobs, Harvey Rubin, Arnab K. Chatterjee, Feng Wang

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nm against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target.

Original languageEnglish (US)
Pages (from-to)3478-3482
Number of pages5
JournalAngewandte Chemie - International Edition
Volume57
Issue number13
DOIs
Publication statusPublished - Mar 19 2018

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Keywords

  • Mycobaterium tuberculosis
  • Ndh-2
  • antimicrobial compounds
  • drug discovery
  • oxidative phosphorylation

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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