Identification of 4-amino-thieno[2,3-d]pyrimidines as QcrB inhibitors in Mycobacterium tuberculosis

Gregory A. Harrison, Anne E. Mayer Bridwell, Megh Singh, Keshav Jayaraman, Leslie A. Weiss, Rachel L. Kinsella, Janessa S. Aneke, Kelly Flentie, Miranda E. Schene, Margaret Gaggioli, Samantha D. Solomon, Scott A. Wildman, Marvin J. Meyers, Christina L. Stallings

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by Mycobacterium tuberculosis. Of the 10 million cases of tuberculosis in 2017, approximately 19% of new cases and 43% of previously treated cases were caused by strains of M. tuberculosis resistant to at least one frontline antibiotic. There is a clear need for new therapies that target these genetically resistant strains. Here, we report the discovery of a new series of antimycobacterial compounds, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit the growth of M. tuberculosis. To elucidate the mechanism by which these compounds inhibit M. tuberculosis, we selected for mutants resistant to a representative 4-amino-thieno[2,3-d]pyrimidine and sequenced these strains to identify the mutations that confer resistance. We isolated a total of 12 resistant mutants, each of which harbored a nonsynonymous mutation in the gene qcrB, which encodes a subunit of the electron transport chain (ETC) enzyme cytochrome bc1 oxidoreductase, leading us to hypothesize that 4-amino-thieno[2,3-d]pyrimidines target this enzyme complex. We found that addition of 4-amino-thieno[2,3-d]pyrimidines to M. tuberculosis cultures resulted in a decrease in ATP levels, supporting our model that these compounds inhibit the M. tuberculosis ETC. Furthermore, 4-amino-thieno[2,3-d]pyrimidines had enhanced activity against a mutant of M. tuberculosis deficient in cytochrome bd oxidase, which is a hallmark of cytochrome bc1 inhibitors. Therefore, 4-aminothieno[ 2,3-d]pyrimidines represent a novel series of QcrB inhibitors that build on the growing number of chemical scaffolds that are able to inhibit the mycobacterial cytochrome bc1 complex.

Original languageEnglish
Article numbere00606-19
JournalmSphere
Volume4
Issue number5
DOIs
StatePublished - 2019

Keywords

  • Antibiotic
  • CydAB
  • Cytochrome
  • Drug discovery
  • Mycobacterium tuberculosis
  • QcrB
  • Respiration

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