Pyrazinoic acid inhibits a bifunctional enzyme in Mycobacterium tuberculosis

Moses Njire, Na Wang, Bangxing Wang, Yaoju Tan, Xingshan Cai, Yanwen Liu, Julius Mugweru, Jintao Guo, H. M.Adnan Hameed, Shouyong Tan, Jianxiong Liu, Wing Wai Yew, Eric Nuermberger, Gyanu Lamichhane, Jinsong Liu, Tianyu Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug into pyrazinoic acid (POA) by Mycobacterium tuberculosis has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report how a new PZA resistance determinant, the Asp67Asn substitution in Rv2783, confers M. tuberculosis resistance to PZA. Expression of the mutant allele but not the wild-type allele in M. tuberculosis recapitulates the PZA resistance observed in clinical isolates. In addition to catalyzing the metabolism of RNA and single-stranded DNA, Rv2783 also metabolized ppGpp, an important signal transducer involved in the stringent response in bacteria. All catalytic activities of the wild-type Rv2783 but not the mutant were significantly inhibited by POA. These results, which indicate that Rv2783 is a target of PZA, provide new insight into the molecular mechanism of the sterilizing activity of this drug and a basis for improving the molecular diagnosis of PZA resistance and developing evolved PZA derivatives to enhance its antituberculosis activity.

Original languageEnglish (US)
Article numbere00070-17
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number7
DOIs
StatePublished - Jul 2017

Keywords

  • Antibiotic resistance
  • Drug target
  • PNPase
  • PpGpp
  • Pyrazinamide
  • Pyrazinoic acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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