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Dissecting vancomycin-intermediate resistance in staphylococcus aureus using genome-wide association

Md Tauqeer Alam1, Robert A Petit1, Emily K Crispell2

  • 1Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine.

Genome Biology and Evolution
|May 3, 2014
PubMed

Insights

Whole-genome analysis identified a key mutation in the rpoB gene associated with vancomycin-intermediate Staphylococcus aureus (VISA) resistance. Rare mutations in other genes also contribute to VISA, aiding in resistance prediction.

Area of Science:

  • Microbiology
  • Genomics
  • Antimicrobial Resistance

Background:

  • Vancomycin-intermediate Staphylococcus aureus (VISA) poses a significant clinical challenge.
  • VISA is characterized by a minimal inhibitory concentration (MIC) of 4-8 µg/ml.
  • VISA development involves genetic alterations in multiple loci, with over 16 candidate genes identified.

Purpose of the Study:

  • To conduct a whole-genome comparative analysis of vancomycin-sensitive and VISA strains.
  • To identify genetic variations associated with vancomycin resistance in S. aureus.
  • To develop a predictive model for the VISA phenotype.

Main Methods:

  • Whole-genome comparative analysis of 49 vancomycin-sensitive and 26 VISA S. aureus strains.
  • Determination of vancomycin resistance using broth microdilution, Etest, and PAP-AUC.
  • Genome-wide association studies (GWAS) to identify significant genetic associations.

Main Results:

  • A highly significant association (P = 8.78 E-08) was found between a nonsynonymous mutation at codon 481 (H481) of the rpoB gene and increased vancomycin MIC.
  • Rare mutations in candidate genes (walKR, vraSR, graSR, agrA) were identified using public genome databases.
  • A preliminary predictive model (ECM+RMCG) achieved 81% accuracy and 73% sensitivity for VISA prediction.
  • The level of vancomycin resistance positively correlated with the number of identified mutations.

Conclusions:

  • GWAS is a powerful tool for identifying common genetic variants linked to antibiotic resistance in bacteria.
  • Rare mutations in specific candidate genes, discoverable through large genomic datasets, are also associated with antibiotic resistance phenotypes.
  • The findings contribute to a better understanding of VISA evolution and provide a basis for improved diagnostic and therapeutic strategies.
Keywords:
bacteriagenomicsphylogenywhole-genome sequencing

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