Mycobacterium tuberculosis Pyrazinamide Resistance Determinants: a Multicenter Study
Author(s)
Type
Journal Article
Abstract
Pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid by the enzyme pyrazinamidase, encoded by the pncA gene in Mycobacterium tuberculosis. Molecular identification of mutations in pncA offers the potential for rapid detection of pyrazinamide resistance (PZAr). However, the genetic variants are highly variable and scattered over the full length of pncA, complicating the development of a molecular test. We performed a large multicenter study assessing pncA sequence variations in 1,950 clinical isolates, including 1,142 multidrug-resistant (MDR) strains and 483 fully susceptible strains. The results of pncA sequencing were correlated with phenotype, enzymatic activity, and structural and phylogenetic data. We identified 280 genetic variants which were divided into four classes: (i) very high confidence resistance mutations that were found only in PZAr strains (85%), (ii) high-confidence resistance mutations found in more than 70% of PZAr strains, (iii) mutations with an unclear role found in less than 70% of PZAr strains, and (iv) mutations not associated with phenotypic resistance (10%). Any future molecular diagnostic assay should be able to target and identify at least the very high and high-confidence genetic variant markers of PZAr; the diagnostic accuracy of such an assay would be in the range of 89.5 to 98.8%.
Date Issued
2014-10-21
Date Acceptance
2014-09-26
Citation
mBio, 2014, 5 (5)
ISSN
2150-7511
Publisher
American Society for Microbiology
Journal / Book Title
mBio
Volume
5
Issue
5
Copyright Statement
© 2014 Miotto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported
license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited
license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
ANTITUBERCULOSIS DRUGS
MIRU-VNTRPLUS
SUSCEPTIBILITY
COMPLEX
CHEMOTHERAPY
MUTATIONS
ASSAY
PNCA
ACCURACY
SYSTEM
Publication Status
Published
Article Number
ARTN e01819-14