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Antimicrob Agents Chemother. 2017 Jul 25;61(8). pii: e00940-17. doi: 10.1128/AAC.00940-17. Print 2017 Aug.

Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis.

Author information

1
Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
2
Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China yzhang@jhsph.edu zhangwenhong@fudan.edu.cn.
3
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

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.

KEYWORDS:

M. tuberculosis proteome microarray; Mycobacterium tuberculosis; efflux pump; overexpression; pyrazinamide resistance

PMID:
28584158
PMCID:
PMC5527661
DOI:
10.1128/AAC.00940-17
[Indexed for MEDLINE]
Free PMC Article

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