A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide

Adam N. Yadon, Kashmeel Maharaj, John H. Adamson, Yi-Pin Lai, James C. Sacchettini, Thomas R. Ioerger, Eric J. Rubin () and Alexander S. Pym ()
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Adam N. Yadon: Harvard T.H. Chan School of Public Health
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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00721-2

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