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. 2017 Oct 11;18(1):769.
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  1 , David Requena  1 , Eduardo Gushiken  1 , Robert H Gilman  2 , Ricardo Antiparra  1 , Bryan Lucero  1 , Pilar Lizárraga  1 , Basilio Cieza  1 , Elisa Roncal  1 , Louis Grandjean  3 , Arnab Pain  4 , Ruth McNerney  5 , Taane G Clark  5   6 , David Moore  5 , Mirko Zimic  7
Affiliations

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

Patricia Sheen et al. BMC Genomics. .

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords: Drugs; Efflux pump; Genes; Genome; MDR; Metallochaperone; Mutations; Pyrazinamide; Resistance; Tuberculosis.

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Conflict of interest statement

Ethics approval and consent to participate

Ethical approval for samples collection and sequencing was obtained from the Institutional Ethics Committee of Universidad Peruana Cayetano Heredia and The London School of Hygiene and Tropical Medicine. Institutional approval was obtained from the Peruvian Ministry of Health. Written informed consent was obtained from all of the enrolled patients. The samples form part of a multi-center drug resistance study (pathogenseq.lshtm.ac.uk/gdrs).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Distances-based tree based on spoligotyping profile of the strains
Fig. 2
Fig. 2
Histogram with standard errors of the strains in the study, according their SIT code. In black (PZA resistant strains), in white (PZA susceptible strains)
See this image and copyright information in PMC

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