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The Stringent Response Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection

Liang Li1, Arnold S Bayer1,2,3, Ambrose Cheung4

  • 1Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.

The Journal of Infectious Diseases
|April 26, 2020
PubMed

Insights

Persistent methicillin-resistant Staphylococcus aureus (MRSA) infections are challenging due to antibiotic treatment failures. This study reveals that higher (p)ppGpp production and specific genetic mechanisms in persistent MRSA contribute to treatment failure.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Genetics

Background:

  • Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections pose a significant clinical challenge, often leading to antibiotic treatment failure.
  • Failures occur even when MRSA strains appear susceptible to antibiotics in vitro, indicating underlying adaptive mechanisms.

Purpose of the Study:

  • To investigate the role of purine biosynthesis pathways and stringent response mechanisms in persistent MRSA infections.
  • To compare genetic and phenotypic characteristics of persistent (PB) and resolving (RB) MRSA clinical isolates.

Main Methods:

  • Utilized genetically matched persistent and resolving MRSA clinical bacteremia isolates and isogenic MRSA strain sets.
  • Analyzed (p)ppGpp production, phenol-soluble-modulin expression, polymorphonuclear leukocyte interactions, and fibronectin/endothelial cell adherence and damage.
  • Employed an experimental endocarditis model with isogenic strains (JE2 parental, relP-mutant, relP-complemented) to assess outcomes.

Main Results:

  • Persistent MRSA isolates exhibited significantly higher (p)ppGpp production compared to resolving isolates.
  • PB isolates showed increased phenol-soluble-modulin expression, enhanced polymorphonuclear leukocyte lysis and survival, and greater fibronectin/endothelial cell adherence and damage.
  • Isogenic strains demonstrated significant outcome differences in the endocarditis model, correlating with observed molecular differences.

Conclusions:

  • Purine biosynthesis is significantly regulated by the stringent response in MRSA.
  • Findings suggest a novel adaptive genetic mechanism contributing to persistent MRSA infections and treatment failure.
Keywords:
MRSA(p)ppGppendovascular infectionpersistencepurine biosynthesisstringent response

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