The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD

Sun, Qingan; Li, Xiaojun; Perez, Lisa M.; Shi, Wanliang; Zhang, Ying; Sacchettini, James C.

doi:10.1038/s41467-019-14238-3

Title: The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD

Journal Article · Fri Jan 17 00:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-14238-3· OSTI ID:1603168

^[1]; Li, Xiaojun ^[1];

^[1]; Shi, Wanliang ^[2]; Zhang, Ying ^[2]; Sacchettini, James C. ^[1]

Texas A & M Univ., College Station, TX (United States)
Johns Hopkins Univ., Baltimore, MD (United States)

Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH)

OSTI ID:: 1603168

Journal Information:: Nature Communications, Vol. 11, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 25 works

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