Pyrazinoic acid inhibits the bifunctional enzyme (Rv2783) in mycobacterium tuberculosis by competing with tmRNA

Lei He; Peng Cui; Wanliang Shi; Qiong Li; Wenhong Zhang; Min Li; Ying Zhang

doi:10.3390/pathogens8040230

Pyrazinoic acid inhibits the bifunctional enzyme (Rv2783) in mycobacterium tuberculosis by competing with tmRNA

Lei He, Peng Cui, Wanliang Shi, Qiong Li, Wenhong Zhang, Min Li, Ying Zhang

Bloomberg School of Public Health

Research output: Contribution to journal › Article

Abstract

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.

Original language	English (US)
Article number	230
Journal	Pathogens
Volume	8
Issue number	4
DOIs	https://doi.org/10.3390/pathogens8040230
State	Published - Dec 2019

Keywords

Mycobacterium tuberculosis
PNPase
Pyrazinamide resistance
Rv2783c gene
TmRNA

ASJC Scopus subject areas

Immunology and Allergy
Molecular Biology
Immunology and Microbiology(all)
Microbiology (medical)
Infectious Diseases

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He, L., Cui, P., Shi, W., Li, Q., Zhang, W., Li, M., & Zhang, Y. (2019). Pyrazinoic acid inhibits the bifunctional enzyme (Rv2783) in mycobacterium tuberculosis by competing with tmRNA. Pathogens, 8(4), [230]. https://doi.org/10.3390/pathogens8040230

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title = "Pyrazinoic acid inhibits the bifunctional enzyme (Rv2783) in mycobacterium tuberculosis by competing with tmRNA",

abstract = "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.",

keywords = "Mycobacterium tuberculosis, PNPase, Pyrazinamide resistance, Rv2783c gene, TmRNA",

author = "Lei He and Peng Cui and Wanliang Shi and Qiong Li and Wenhong Zhang and Min Li and Ying Zhang",

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AU - He, Lei

AU - Cui, Peng

AU - Shi, Wanliang

AU - Li, Qiong

AU - Zhang, Wenhong

AU - Li, Min

AU - Zhang, Ying

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

KW - Mycobacterium tuberculosis

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KW - Pyrazinamide resistance

KW - Rv2783c gene

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