Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis

Michelle Yee; Pooja Gopal; Thomas Dick

doi:10.1128/AAC.02342-16

Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2017 Jan 24;61(2):e02342-16. doi: 10.1128/AAC.02342-16. Print 2017 Feb.

Authors

Michelle Yee¹, Pooja Gopal¹, Thomas Dick²

Affiliations

¹ Antibacterial Drug Discovery Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
² Antibacterial Drug Discovery Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore [email protected].

Abstract

Previously, we showed that mutations in Mycobacterium tuberculosis panD, involved in coenzyme A biosynthesis, cause resistance against pyrazinoic acid, the bioactive component of the prodrug pyrazinamide. To identify additional resistance mechanisms, we isolated mutants resistant against pyrazinoic acid and subjected panD wild-type strains to whole-genome sequencing. Eight of the nine resistant strains harbored missense mutations in the unfoldase ClpC1 associated with the caseinolytic protease complex.

Keywords: ClpC1; Mycobacterium tuberculosis; caseinolytic protease; pyrazinamide; resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology*
Drug Resistance, Bacterial / genetics
Microbial Sensitivity Tests
Mutation / genetics
Mutation, Missense / genetics*
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / genetics*
Pyrazinamide / analogs & derivatives
Pyrazinamide / pharmacology*

Substances

Antitubercular Agents
Pyrazinamide
pyrazinoic acid