Identification of novel efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c involved in pyrazinamide resistance in Mycobacterium tuberculosis

Yumeng Zhang, Jia Zhang, Peng Cui, Ying Zhang, Wenhong Zhang

Research output: Contribution to journalArticle

Abstract

Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1 mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an M. tuberculosis proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis. Future studies are needed to assess their roles in PZA resistance in clinical strains.

Original languageEnglish (US)
Article numbere00940
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number8
DOIs
StatePublished - Aug 1 2017

Keywords

  • Efflux pump
  • M. tuberculosis proteome microarray
  • Mycobacterium tuberculosis
  • Overexpression
  • Pyrazinamide resistance

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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