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The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD

Author

Listed:
  • Qingan Sun

    (Texas A&M University)

  • Xiaojun Li

    (Texas A&M University)

  • Lisa M. Perez

    (Texas A&M University)

  • Wanliang Shi

    (Bloomberg School of Public Health, Johns Hopkins University)

  • Ying Zhang

    (Bloomberg School of Public Health, Johns Hopkins University)

  • James C. Sacchettini

    (Texas A&M University)

Abstract

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.

Suggested Citation

  • Qingan Sun & Xiaojun Li & Lisa M. Perez & Wanliang Shi & Ying Zhang & James C. Sacchettini, 2020. "The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD," Nature Communications, Nature, vol. 11(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14238-3
    DOI: 10.1038/s41467-019-14238-3
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    Cited by:

    1. Rydberg Roman Supo-Escalante & Aldhair Médico & Eduardo Gushiken & Gustavo E Olivos-Ramírez & Yaneth Quispe & Fiorella Torres & Melissa Zamudio & Ricardo Antiparra & L Mario Amzel & Robert H Gilman & , 2020. "Prediction of Mycobacterium tuberculosis pyrazinamidase function based on structural stability, physicochemical and geometrical descriptors," PLOS ONE, Public Library of Science, vol. 15(7), pages 1-26, July.

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