A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis

Abstract Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative test...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	S. M. Ramirez-Busby, T. C. Rodwell, L. Fink, D. Catanzaro, R. L. Jackson, M. Pettigrove, A. Catanzaro, F. Valafar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9ddabba880874e6baaf3b9faa351eb0a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9ddabba880874e6baaf3b9faa351eb0a
record_format	dspace
spelling	oai:doaj.org-article:9ddabba880874e6baaf3b9faa351eb0a2021-12-02T12:32:57ZA Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis10.1038/s41598-017-03452-y2045-2322https://doaj.org/article/9ddabba880874e6baaf3b9faa351eb0a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03452-yhttps://doaj.org/toc/2045-2322Abstract Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne’s assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8–10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance.S. M. Ramirez-BusbyT. C. RodwellL. FinkD. CatanzaroR. L. JacksonM. PettigroveA. CatanzaroF. ValafarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q S. M. Ramirez-Busby T. C. Rodwell L. Fink D. Catanzaro R. L. Jackson M. Pettigrove A. Catanzaro F. Valafar A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
description	Abstract Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne’s assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8–10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance.
format	article
author	S. M. Ramirez-Busby T. C. Rodwell L. Fink D. Catanzaro R. L. Jackson M. Pettigrove A. Catanzaro F. Valafar
author_facet	S. M. Ramirez-Busby T. C. Rodwell L. Fink D. Catanzaro R. L. Jackson M. Pettigrove A. Catanzaro F. Valafar
author_sort	S. M. Ramirez-Busby
title	A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
title_short	A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
title_full	A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
title_fullStr	A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
title_full_unstemmed	A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
title_sort	multinational analysis of mutations and heterogeneity in pzase, rpsa, and pand associated with pyrazinamide resistance in m/xdr mycobacterium tuberculosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9ddabba880874e6baaf3b9faa351eb0a
work_keys_str_mv	AT smramirezbusby amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT tcrodwell amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT lfink amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT dcatanzaro amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT rljackson amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT mpettigrove amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT acatanzaro amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT fvalafar amultinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT smramirezbusby multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT tcrodwell multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT lfink multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT dcatanzaro multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT rljackson multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT mpettigrove multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT acatanzaro multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis AT fvalafar multinationalanalysisofmutationsandheterogeneityinpzaserpsaandpandassociatedwithpyrazinamideresistanceinmxdrmycobacteriumtuberculosis
_version_	1718393935515090944

A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis

Ejemplares similares