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Distribution of Common and Rare Genetic Markers of Second-Line-Injectable-Drug Resistance in Mycobacterium

Derek Conkle-Gutierrez1, Calvin Kim1, Sarah M Ramirez-Busby1

  • 1Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence (LPCDRP), Biomedical Informatics Research Center, Division of Epidemiology, School of Public Health, San Diego State Universitygrid.263081.e, San Diego, California, USA.

Antimicrobial Agents and Chemotherapy
|May 9, 2022
PubMed

Insights

Genomic markers in Mycobacterium tuberculosis explain most second-line injectable drug resistance. However, novel mutations in genes like whiB7 and Rv2680-Rv2681 are linked to unexplained resistance, impacting treatment decisions.

Area of Science:

  • Genetics and Genomics
  • Microbiology
  • Drug Resistance

Background:

  • Second-line injectable drugs (SLIDs) like amikacin, capreomycin, and kanamycin are crucial for treating multidrug-resistant tuberculosis.
  • Canonical mutations in the rrs gene and eis promoter are primary drivers of SLID resistance, but alternative mechanisms exist.
  • Understanding all resistance mechanisms is vital for effective treatment and diagnostics.

Purpose of the Study:

  • To investigate genomic markers associated with phenotypic resistance to amikacin, capreomycin, and kanamycin in clinical Mycobacterium tuberculosis isolates.
  • To identify canonical and novel genetic mutations conferring resistance to SLIDs.
  • To evaluate the contribution of different mutations to SLID resistance.

Main Methods:

  • Genomic DNA was analyzed from 1,184 clinical Mycobacterium tuberculosis isolates from 7 countries.
  • Genotyping focused on known resistance-conferring mutations in rrs and eis.
  • Genome-wide association study (GWAS) was employed to identify novel resistance markers.

Main Results:

  • Canonical mutations in rrs (A1401G, G1484T) and eis promoter (G-10A, C-12T, C-14T) were strongly associated with SLID resistance.
  • Canonical mutations accounted for the majority of amikacin, capreomycin, and kanamycin resistance.
  • 103 isolates showed phenotypic resistance unexplained by canonical mutations; GWAS identified whiB7 and Rv2680-Rv2681 promoter mutations associated with kanamycin and capreomycin resistance, respectively.

Conclusions:

  • While canonical mutations are key, a significant proportion of SLID resistance is due to other genetic factors.
  • Mutations in whiB7 and the Rv2680-Rv2681 operon promoter represent novel mechanisms of kanamycin and capreomycin resistance.
  • Aggregating mutations by gene aids in identifying rare resistance mechanisms, crucial for refining molecular diagnostics and treatment strategies.
Keywords:
Mycobacterium tuberculosisamikacincapreomycindrug resistanceinjectableskanamycinrare mechanismssecond-line antibiotics

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