Role of Alanine Racemase Mutations in Mycobacterium Tuberculosis d-Cycloserine Resistance

Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01575-17. doi: 10.1128/AAC.01575-17. Print 2017 Dec.

Abstract

A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine.

Keywords: Mycobacterium tuberculosis; alanine racemase; cycloserine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Racemase / genetics*
  • Alanine Racemase / metabolism
  • Antibiotics, Antitubercular / pharmacology
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Cycloserine / pharmacology*
  • Drug Resistance, Bacterial / genetics*
  • Evolution, Molecular
  • Gene Expression
  • Microbial Sensitivity Tests
  • Mutation*
  • Mycobacterium tuberculosis / classification
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / genetics*
  • Phylogeny
  • Selection, Genetic

Substances

  • Antibiotics, Antitubercular
  • Bacterial Proteins
  • Cycloserine
  • Alanine Racemase