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Mutated response regulator graR is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous

Hui-min Neoh1, Longzhu Cui, Harumi Yuzawa

  • 1Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, Japan 113-8421.

Antimicrobial Agents and Chemotherapy
|October 24, 2007
PubMed

Insights

A mutation in the graR gene drives the progression from heterogeneous vancomycin resistance (hetero-VISA) to vancomycin-intermediate Staphylococcus aureus (VISA). This graR* mutation specifically enhances vancomycin resistance in hetero-VISA strains.

Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) requires multistep genetic changes to develop vancomycin resistance.
  • Heterogeneous vancomycin-intermediate S. aureus (hetero-VISA) represents an intermediate stage in this resistance progression.

Purpose of the Study:

  • To identify genetic factors contributing to the development of vancomycin resistance in MRSA.
  • To investigate the role of the graSR two-component system in vancomycin resistance.

Main Methods:

  • Whole-genome sequencing of MRSA strains Mu3 (hetero-VISA), Mu50 (VISA), and N315 (vancomycin-susceptible S. aureus [VSSA]).
  • Genetic manipulation to introduce mutated graR (graR*) and intact graR (graRn) into bacterial strains.
  • Determination of minimum inhibitory concentrations (MICs) for vancomycin, daptomycin, and oxacillin.

Main Results:

  • A mutation in the graR gene (response regulator of the graSR system) was identified in the hetero-VISA strain Mu3.
  • Introduction of graR* converted the hetero-VISA phenotype of Mu3 to a VISA phenotype, while intact graRn did not.
  • graR* expression enhanced vancomycin resistance in hetero-VISA but not VSSA, suggesting a specific physiological context is required.
  • Overexpression of graR* increased daptomycin MICs and decreased oxacillin MICs in both Mu3 and N315 strains.

Conclusions:

  • The graR* mutation is a key factor in the transition from hetero-VISA to VISA.
  • The graSR system plays a critical role in modulating antibiotic resistance in Staphylococcus aureus.
  • graR* influences resistance to multiple antibiotics, including vancomycin, daptomycin, and oxacillin.

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