A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

Patricia Sheen; David Requena; Eduardo Gushiken; Robert H. Gilman; Ricardo Antiparra; Bryan Lucero; Pilar Lizárraga; Basilio Cieza; Elisa Roncal; Louis Grandjean; Arnab Pain; Ruth McNerney; Taane G. Clark; David J. Moore; Mirko Zimic

doi:10.1186/s12864-017-4146-z

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

Patricia Sheen, David Requena, Eduardo Gushiken, Robert H. Gilman, Ricardo Antiparra, Bryan Lucero, Pilar Lizárraga, Basilio Cieza, Elisa Roncal, Louis Grandjean, Arnab Pain, Ruth McNerney, Taane G. Clark, David J. Moore, Mirko Zimic

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Abstract

Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

Original language	English (US)
Journal	BMC Genomics
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12864-017-4146-z
State	Published - Oct 11 2017

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https://repository.kaust.edu.sa/bitstream/10754/625883/1/document.pdf

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Sheen, P., Requena, D., Gushiken, E., Gilman, R. H., Antiparra, R., Lucero, B., Lizárraga, P., Cieza, B., Roncal, E., Grandjean, L., Pain, A., McNerney, R., Clark, T. G., Moore, D. J., & Zimic, M. (2017). A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance. BMC Genomics, 18(1). https://doi.org/10.1186/s12864-017-4146-z

@article{1db861dc1d5549ceb225230626bb8e46,

title = "A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance",

abstract = "Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.",

author = "Patricia Sheen and David Requena and Eduardo Gushiken and Gilman, {Robert H.} and Ricardo Antiparra and Bryan Lucero and Pilar Liz{\'a}rraga and Basilio Cieza and Elisa Roncal and Louis Grandjean and Arnab Pain and Ruth McNerney and Clark, {Taane G.} and Moore, {David J.} and Mirko Zimic",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: Some of this research and some members of the research team were funded by the Wellcome Trust (award 099805/Z/12/Z); the charity IFHAD: Innovation For Health And Development; DFID-CSCF; the Joint Global Health Trials consortium (MRC, DFID & Wellcome Trust); the Imperial College Biomedical Research Centre; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health US, under the terms of Award 1R01TW008669-01. This study was also partially funded by L{\'o}real UNESCO, TWAS and Grand Challenge Canada. PS is a Wellcome Trust fellow. TGC receives funding from the MRC UK (MR/K000551/1, MR/M01360X/1, MR/N010469/1, MC_PC_15103). AP is supported by faculty baseline research fund from KAUST. MZ is a Bill and Melinda Gates Foundation grantee.",

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doi = "10.1186/s12864-017-4146-z",

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Sheen, P, Requena, D, Gushiken, E, Gilman, RH, Antiparra, R, Lucero, B, Lizárraga, P, Cieza, B, Roncal, E, Grandjean, L, Pain, A, McNerney, R, Clark, TG, Moore, DJ & Zimic, M 2017, 'A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance', BMC Genomics, vol. 18, no. 1. https://doi.org/10.1186/s12864-017-4146-z

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T1 - A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

AU - Sheen, Patricia

AU - Requena, David

AU - Gushiken, Eduardo

AU - Gilman, Robert H.

AU - Antiparra, Ricardo

AU - Lucero, Bryan

AU - Lizárraga, Pilar

AU - Cieza, Basilio

AU - Roncal, Elisa

AU - Grandjean, Louis

AU - Pain, Arnab

AU - McNerney, Ruth

AU - Clark, Taane G.

AU - Moore, David J.

AU - Zimic, Mirko

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: Some of this research and some members of the research team were funded by the Wellcome Trust (award 099805/Z/12/Z); the charity IFHAD: Innovation For Health And Development; DFID-CSCF; the Joint Global Health Trials consortium (MRC, DFID & Wellcome Trust); the Imperial College Biomedical Research Centre; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health US, under the terms of Award 1R01TW008669-01. This study was also partially funded by Lóreal UNESCO, TWAS and Grand Challenge Canada. PS is a Wellcome Trust fellow. TGC receives funding from the MRC UK (MR/K000551/1, MR/M01360X/1, MR/N010469/1, MC_PC_15103). AP is supported by faculty baseline research fund from KAUST. MZ is a Bill and Melinda Gates Foundation grantee.

PY - 2017/10/11

Y1 - 2017/10/11

N2 - Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

AB - Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

UR - http://hdl.handle.net/10754/625883

UR - https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4146-z

UR - http://www.scopus.com/inward/record.url?scp=85030830645&partnerID=8YFLogxK

U2 - 10.1186/s12864-017-4146-z

DO - 10.1186/s12864-017-4146-z

M3 - Article

C2 - 29020922

SN - 1471-2164

VL - 18

JO - BMC Genomics

JF - BMC Genomics

IS - 1

ER -

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

Abstract

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