Pyrazinoic Acid Inhibits a Bifunctional Enzyme in Mycobacterium tuberculosis

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 has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2017-07, Vol.61 (7)
Main Authors: Njire, Moses, Wang, Na, Wang, Bangxing, Tan, Yaoju, Cai, Xingshan, Liu, Yanwen, Mugweru, Julius, Guo, Jintao, Hameed, H M Adnan, Tan, Shouyong, Liu, Jianxiong, Yew, Wing Wai, Nuermberger, Eric, Lamichhane, Gyanu, Liu, Jinsong, Zhang, Tianyu
Format: Article
Language:English
Subjects:
Antitubercular Agents
Antitubercular Agents - pharmacology
Chromatography, High Pressure Liquid
DNA, Single-Stranded - genetics
Drug Resistance, Bacterial
Mechanisms of Resistance
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - enzymology
Pyrazinamide
Pyrazinamide - analogs & derivatives
Pyrazinamide - pharmacology
Pyrophosphatases - genetics
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Summary: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 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 resistance to PZA. Expression of the mutant allele but not the wild-type allele in 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.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00070-17