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A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide

Author

Listed:
  • Adam N. Yadon

    (Harvard T.H. Chan School of Public Health
    Nelson R. Mandela School of Medicine)

  • Kashmeel Maharaj

    (Nelson R. Mandela School of Medicine)

  • John H. Adamson

    (Nelson R. Mandela School of Medicine)

  • Yi-Pin Lai

    (3112 Texas A&M University)

  • James C. Sacchettini

    (Texas A&M University)

  • Thomas R. Ioerger

    (3112 Texas A&M University)

  • Eric J. Rubin

    (Harvard T.H. Chan School of Public Health)

  • Alexander S. Pym

    (Nelson R. Mandela School of Medicine)

Abstract

Tuberculosis chemotherapy is dependent on the use of the antibiotic pyrazinamide, which is being threatened by emerging drug resistance. Resistance is mediated through mutations in the bacterial gene pncA. Methods for testing pyrazinamide susceptibility are difficult and rarely performed, and this means that the full spectrum of pncA alleles that confer clinical resistance to pyrazinamide is unknown. Here, we performed in vitro saturating mutagenesis of pncA to generate a comprehensive library of PncA polymorphisms resultant from a single-nucleotide polymorphism. We then screened it for pyrazinamide resistance both in vitro and in an infected animal model. We identify over 300 resistance-conferring substitutions. Strikingly, these mutations map throughout the PncA structure and result in either loss of enzymatic activity and/or decrease in protein abundance. Our comprehensive mutational and screening approach should stand as a paradigm for determining resistance mutations and their mechanisms of action.

Suggested Citation

  • Adam N. Yadon & Kashmeel Maharaj & John H. Adamson & Yi-Pin Lai & James C. Sacchettini & Thomas R. Ioerger & Eric J. Rubin & Alexander S. Pym, 2017. "A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00721-2
    DOI: 10.1038/s41467-017-00721-2
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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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