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ClpP-independent function of ClpX interferes with telithromycin resistance conferred by Msr(A) in Staphylococcus

Vladimir Vimberg1, Jakub Lenart1, Jiri Janata1

  • 1Institute of Microbiology, The Czech Academy of Sciences, Prague, Czech Republic.

Antimicrobial Agents and Chemotherapy
|March 25, 2015
PubMed

Insights

Mutations in ClpX, a protein involved in bacterial protein degradation, enhance resistance to ketolide antibiotics like telithromycin in staphylococci. This effect of ClpX on macrolide resistance protein A (MsrA) occurs independently of the ClpP protease.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Antibiotic Resistance

Background:

  • The macrolide resistance protein A (MsrA) confers resistance to macrolide antibiotics in staphylococci.
  • MsrA provides high resistance to macrolides but only low resistance to ketolides, such as telithromycin.

Purpose of the Study:

  • To investigate the role of the ClpXP proteolytic system in modulating MsrA-mediated antibiotic resistance.
  • To determine if ClpX or ClpP is responsible for altering resistance levels to ketolides.

Main Methods:

  • Genetic manipulation of Staphylococcus strains to create clpX and clpP knockout mutants.
  • Assessment of antibiotic resistance levels (specifically to telithromycin) in strains expressing MsrA with altered ClpX or ClpP function.
  • Analysis of MsrA-mediated resistance in the presence and absence of functional ClpX and ClpP components.

Main Results:

  • Mutations in conserved functional regions of ClpX, or complete deletion of clpX, significantly increased MsrA-mediated resistance to telithromycin.
  • Deletion of clpP did not affect MsrA-mediated resistance to telithromycin.
  • The observed increase in ketolide resistance was dependent on ClpX function, independent of the ClpP protease.

Conclusions:

  • ClpX, the chaperone component of the ClpXP system, plays a crucial role in regulating MsrA-mediated resistance to ketolides.
  • ClpX modulates MsrA function independently of the ClpP protease, suggesting a direct or indirect interaction affecting antibiotic binding or efflux.
  • Targeting ClpX could be a potential strategy to overcome ketolide resistance in staphylococcal infections.

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