Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide

Wanliang Shi; Peng Cui; Hongxia Niu; Shuo Zhang; Tone Tønjum; Bingdong Zhu; Ying Zhang

doi:10.1128/AAC.02681-18

Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide

Antimicrob Agents Chemother. 2019 May 24;63(6):e02681-18. doi: 10.1128/AAC.02681-18. Print 2019 Jun.

Authors

Wanliang Shi¹, Peng Cui¹, Hongxia Niu^{2

3}, Shuo Zhang¹, Tone Tønjum^{4

5}, Bingdong Zhu^{2

3}, Ying Zhang⁶

Affiliations

¹ Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
² Lanzhou Center for Tuberculosis Research and Institute of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
³ Gansu Provincial Key Laboratory of Evidence Based Medicine and Clinical Translation, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
⁴ Department of Microbiology, University of Oslo, Oslo, Norway.
⁵ Unit for Genome Dynamics, Department of Microbiology, Oslo University Hospital, Oslo, Norway.
⁶ Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA yzhang@jhsph.edu.

Abstract

Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the Mycobacterium tuberculosis chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.

Keywords: Mycobacterium tuberculosis; RpsA; drug resistance mechanisms; pyrazinamide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology*
Chromosomes, Bacterial / genetics*
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects
Mycobacterium tuberculosis / genetics*
Point Mutation / genetics
Pyrazinamide / pharmacology*

Substances

Antitubercular Agents
Pyrazinamide

Grants and funding

R01 AI099512/AI/NIAID NIH HHS/United States