Survey of drug resistance associated gene mutations in Mycobacterium tuberculosis, ESKAPE and other bacterial species

Sci Rep. 2020 Jun 2;10(1):8957. doi: 10.1038/s41598-020-65766-8.

Abstract

Tuberculosis treatment includes broad-spectrum antibiotics such as rifampicin, streptomycin and fluoroquinolones, which are also used against other pathogenic bacteria. We developed Drug Resistance Associated Genes database (DRAGdb), a manually curated repository of mutational data of drug resistance associated genes (DRAGs) across ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens, and other bacteria with a special focus on Mycobacterium tuberculosis (MTB). Analysis of mutations in drug-resistant genes listed in DRAGdb suggested both homoplasy and pleiotropy to be associated with resistance. Homoplasy was observed in six genes namely gidB, gyrA, gyrB, rpoB, rpsL and rrs. For these genes, drug resistance-associated mutations at codon level were conserved in MTB, ESKAPE and many other bacteria. Pleiotropy was exemplified by a single nucleotide mutation that was associated with resistance to amikacin, gentamycin, rifampicin and vancomycin in Staphylococcus aureus. DRAGdb data also revealed that mutations in some genes such as pncA, inhA, katG and embA,B,C were specific to Mycobacterium species. For inhA and pncA, the mutations in the promoter region along with those in coding regions were associated with resistance to isoniazid and pyrazinamide respectively. In summary, the DRAGdb database is a compilation of all the major MTB drug resistance genes across bacterial species, which allows identification of homoplasy and pleiotropy phenomena of DRAGs.

Publication types

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

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / genetics
  • DNA, Bacterial / genetics
  • Data Curation / methods
  • Databases, Genetic*
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Extensively Drug-Resistant Tuberculosis / microbiology
  • Fluoroquinolones / therapeutic use
  • Isoniazid / therapeutic use
  • Microbial Sensitivity Tests
  • Mutation / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Pyrazinamide / therapeutic use
  • Rifampin / therapeutic use
  • Sequence Analysis, DNA / methods
  • Tuberculosis, Multidrug-Resistant / drug therapy

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • DNA, Bacterial
  • Fluoroquinolones
  • Pyrazinamide
  • Isoniazid
  • Rifampin