TY - JOUR
T1 - Pyrazinoic acid inhibits the bifunctional enzyme (Rv2783) in mycobacterium tuberculosis by competing with tmRNA
AU - He, Lei
AU - Cui, Peng
AU - Shi, Wanliang
AU - Li, Qiong
AU - Zhang, Wenhong
AU - Li, Min
AU - Zhang, Ying
N1 - Funding Information:
Funding: This work research was funded by the National Natural Science Foundation of China (grant number 81974311) and the Shanghai Pujiang Program (grant no. 2019PJD026) to L.H.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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
KW - PNPase
KW - Pyrazinamide resistance
KW - Rv2783c gene
KW - TmRNA
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U2 - 10.3390/pathogens8040230
DO - 10.3390/pathogens8040230
M3 - Article
C2 - 31718097
AN - SCOPUS:85075065331
VL - 8
JO - Pathogens
JF - Pathogens
SN - 2076-0817
IS - 4
M1 - 230
ER -