Journal article

Structure guided prediction of Pyrazinamide resistance mutations in pncA

Malancha Karmakar, Carlos HM Rodrigues, Kristy Horan, Justin T Denholm, David B Ascher

Scientific Reports | NATURE PUBLISHING GROUP | Published : 2020

Abstract

Pyrazinamide plays an important role in tuberculosis treatment; however, its use is complicated by side-effects and challenges with reliable drug susceptibility testing. Resistance to pyrazinamide is largely driven by mutations in pyrazinamidase (pncA), responsible for drug activation, but genetic heterogeneity has hindered development of a molecular diagnostic test. We proposed to use information on how variants were likely to affect the 3D structure of pncA to identify variants likely to lead to pyrazinamide resistance. We curated 610 pncA mutations with high confidence experimental and clinical information on pyrazinamide susceptibility. The molecular consequences of each mutation on prot..

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Grants

Awarded by Newton Fund RCUK-CONFAP Grant - Medical Research Council (MRC)


Awarded by Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)


Awarded by Jack Brockhoff Foundation


Awarded by National Health and Medical Research Council (NHMRC) of Australia


Funding Acknowledgements

M.K. and C.M.H.R. were funded by the Melbourne Research Scholarship. Funding for genomic sequencing was provided by the Department of Health and Human Services, Victoria. D.B.A. was funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1), the Jack Brockhoff Foundation (JBF 4186, 2016), and an Investigator Grant from the National Health and Medical Research Council (NHMRC) of Australia (GNT1174405). This work was supported in part by the Victorian Government's OIS Program.