Pyrazinoic Acid Inhibits a Bifunctional Enzyme in Mycobacterium tuberculosis [PublishAheadOfPrint]

Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug by Mycobacterium tuberculosis into pyrazinoic acid (POA) has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report a new PZA resistance determinant: Asp67Asn substitution in Rv2783 confers M. tuberculosis resistance to PZA. Expression of the mutant but not the wild-type allele in M. tuberculosis recapitulates PZA resistance observed in clinical isolates. In addition to catalyzing 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 themutant 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 molecular diagnosis of PZA resistance and developing evolved PZA derivatives to enhance its anti-tuberculosis activity.

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