@article{7fb470070e1d4b429fd9ee540cf493b3,
title = "Pyrazinoic acid inhibits a bifunctional enzyme in Mycobacterium tuberculosis",
abstract = "Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug into pyrazinoic acid (POA) by Mycobacterium tuberculosis has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report how a new PZA resistance determinant, the Asp67Asn substitution in Rv2783, confers M. tuberculosis resistance to PZA. Expression of the mutant allele but not the wild-type allele in M. tuberculosis recapitulates the PZA resistance observed in clinical isolates. In addition to catalyzing the metabolism of RNA and single-stranded DNA, Rv2783 also metabolized ppGpp, an important signal transducer involved in the stringent response in bacteria. All catalytic activities of the wild-type Rv2783 but not the mutant were significantly inhibited by POA. These results, which indicate that Rv2783 is a target of PZA, provide new insight into the molecular mechanism of the sterilizing activity of this drug and a basis for improving the molecular diagnosis of PZA resistance and developing evolved PZA derivatives to enhance its antituberculosis activity.",
keywords = "Antibiotic resistance, Drug target, PNPase, PpGpp, Pyrazinamide, Pyrazinoic acid",
author = "Moses Njire and Na Wang and Bangxing Wang and Yaoju Tan and Xingshan Cai and Yanwen Liu and Julius Mugweru and Jintao Guo and Hameed, {H. M.Adnan} and Shouyong Tan and Jianxiong Liu and Yew, {Wing Wai} and Eric Nuermberger and Gyanu Lamichhane and Jinsong Liu and Tianyu Zhang",
note = "Funding Information: We thank Xiantao Zhang at Guangzhou Eggbio Co. Ltd. for helping us with the HPLC analysis of the ppGpp synthetase and hydrolase assay products in this study. This work was supported by the National Natural Science Foundation of China (81572037), by Chinese Academy of Sciences grants (154144KYSB20150045, KFZD-SW- 207), by University of Chinese Academy of Sciences scholarships (to M.N., J.M., H.M.A.H.), by the Ph.D. Start-up Fund of the Natural Science Foundation of Guangdong Province, China (2016A030310123 to J.G.), and a Key Project grant (SKLRD2016ZJ003) from the State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, and was partially supported by the Guangzhou Municipal Industry and Research Collaborative Innovation Program (201508020248, 201604020019), by the National Mega-project of China for Innovative Drugs (2017ZX09201001-003-003), and by the Guangzhou Municipal Clinical Medical Center Program (155700012). Publisher Copyright: Copyright {\textcopyright} 2017 American Society for Microbiology. All Rights Reserved.",
year = "2017",
month = jul,
doi = "10.1128/AAC.00070-17",
language = "English (US)",
volume = "61",
journal = "Antimicrobial agents and chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "7",
}