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

Handle URI:
http://hdl.handle.net/10754/625883
Title:
A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance
Authors:
Sheen, Patricia; Requena, David; Gushiken, Eduardo; Gilman, Robert H.; Antiparra, Ricardo; Lucero, Bryan; Lizárraga, Pilar; Cieza, Basilio; Roncal, Elisa; Grandjean, Louis; Pain, Arnab ( 0000-0002-1755-2819 ) ; McNerney, Ruth; Clark, Taane G.; Moore, David; Zimic, Mirko ( 0000-0002-7203-8847 )
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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Sheen P, Requena D, Gushiken E, Gilman RH, Antiparra R, et al. (2017) A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance. BMC Genomics 18. Available: http://dx.doi.org/10.1186/s12864-017-4146-z.
Publisher:
Springer Nature
Journal:
BMC Genomics
Issue Date:
11-Oct-2017
DOI:
10.1186/s12864-017-4146-z
Type:
Article
ISSN:
1471-2164
Sponsors:
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.
Additional Links:
https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4146-z
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorSheen, Patriciaen
dc.contributor.authorRequena, Daviden
dc.contributor.authorGushiken, Eduardoen
dc.contributor.authorGilman, Robert H.en
dc.contributor.authorAntiparra, Ricardoen
dc.contributor.authorLucero, Bryanen
dc.contributor.authorLizárraga, Pilaren
dc.contributor.authorCieza, Basilioen
dc.contributor.authorRoncal, Elisaen
dc.contributor.authorGrandjean, Louisen
dc.contributor.authorPain, Arnaben
dc.contributor.authorMcNerney, Ruthen
dc.contributor.authorClark, Taane G.en
dc.contributor.authorMoore, Daviden
dc.contributor.authorZimic, Mirkoen
dc.date.accessioned2017-10-17T11:47:39Z-
dc.date.available2017-10-17T11:47:39Z-
dc.date.issued2017-10-11en
dc.identifier.citationSheen P, Requena D, Gushiken E, Gilman RH, Antiparra R, et al. (2017) A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance. BMC Genomics 18. Available: http://dx.doi.org/10.1186/s12864-017-4146-z.en
dc.identifier.issn1471-2164en
dc.identifier.doi10.1186/s12864-017-4146-zen
dc.identifier.urihttp://hdl.handle.net/10754/625883-
dc.description.abstractTuberculosis (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.en
dc.description.sponsorshipSome 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.en
dc.publisherSpringer Natureen
dc.relation.urlhttps://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4146-zen
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectGenomeen
dc.subjectGenesen
dc.subjectResistanceen
dc.subjectTuberculosisen
dc.subjectDrugsen
dc.subjectMDRen
dc.subjectMutationsen
dc.subjectEfflux pumpen
dc.subjectPyrazinamideen
dc.subjectmetallochaperoneen
dc.titleA multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistanceen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalBMC Genomicsen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionLaboratorio de Bioinformática y Biología Molecular. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, San Martín de Porras, 31, Lima, Peru.en
dc.contributor.institutionDepartment of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St., Room 5515, Baltimore, MD, 21205, USA.en
dc.contributor.institutionDepartment of Infection, Immunology and Rheumatology, Institute of Child Health, University College London, 30 Guilford St, London, WC1N 1EH, UK.en
dc.contributor.institutionFaculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.en
dc.contributor.institutionFaculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.en
dc.contributor.institutionLaboratorio de Bioinformática y Biología Molecular. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, San Martín de Porras, 31, Lima, Peru. mirko.zimic@upch.pe.en
kaust.authorPain, Arnaben
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