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Open AccessArticle

Pyrazinoic Acid Inhibits the Bifunctional Enzyme (Rv2783) in Mycobacterium tuberculosis by Competing with tmRNA

1
Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
2
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
3
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
*
Authors to whom correspondence should be addressed.
Pathogens 2019, 8(4), 230; https://doi.org/10.3390/pathogens8040230
Received: 19 September 2019 / Revised: 30 October 2019 / Accepted: 8 November 2019 / Published: 12 November 2019
(This article belongs to the Section Human Pathogens)
Pyrazinamide (PZA) is a key drug for tuberculosis treatment. The active form of PZA, pyrazinoic acid (POA), appears to inhibit multiple targets in M. tuberculosis. Recently, the bifunctional enzyme Rv2783 was reported as a new target of POA. However, the mechanism by which POA inhibits Rv2783 is not yet clear. Here, we report how a new A2104C substitution in Rv2783c, identified in PZA-resistant clinical isolates, conferred resistance to PZA in M. tuberculosis. Expression of the mutant allele recapitulated the PZA resistance. All catalytic activities of Rv2783, but not the mutant, were inhibited by POA. Additionally, POA competed with transfer-messenger RNA (tmRNA) for binding to Rv2783, other than the mutant. These results provide new insight into the molecular mechanism of the antitubercular activity of PZA. View Full-Text
Keywords: mycobacterium tuberculosis; pyrazinamide resistance; Rv2783c gene; PNPase; tmRNA mycobacterium tuberculosis; pyrazinamide resistance; Rv2783c gene; PNPase; tmRNA
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MDPI and ACS Style

He, L.; Cui, P.; Shi, W.; Li, Q.; Zhang, W.; Li, M.; Zhang, Y. Pyrazinoic Acid Inhibits the Bifunctional Enzyme (Rv2783) in Mycobacterium tuberculosis by Competing with tmRNA. Pathogens 2019, 8, 230.

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