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Clinical Rel mutations that increase basal (p)ppGpp promote conjugal transfer of staphylococcal resistance plasmids

Ashley T Deventer1, Ava Sutherland1, Daria Biernacka2

  • 1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, UK.

Microbiology (Reading, England)
|June 9, 2026
PubMed

Insights

Clinical mutations in Staphylococcus aureus Rel protein elevate alarmones (p)ppGpp, promoting antibiotic resistance plasmid transfer. This alarming finding highlights a potential mechanism for the spread of antimicrobial resistance in this deadly pathogen.

Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • Antibiotic resistance genes spread via plasmid conjugation, a significant concern for pathogens like Staphylococcus aureus.
  • Staphylococcus aureus clinical isolates frequently harbor plasmids, facilitating the dissemination of resistance mechanisms.
  • The stringent response, a bacterial stress response, is linked to increased mobile genetic element transfer.

Purpose of the Study:

  • To investigate the role of elevated alarmones guanosine tetra- and pentaphosphate ((p)ppGpp) in promoting conjugal transfer of resistance plasmids in Staphylococcus aureus.
  • To determine if clinical mutations in the stringent response controller, Rel, impact plasmid donation and receipt.
  • To explore the mechanisms underlying the effect of (p)ppGpp on plasmid conjugation.

Main Methods:

  • Analyzing plasmid conjugal transfer frequencies in Staphylococcus aureus strains with clinical Rel mutations.
  • Inducing the stringent response chemically using mupirocin to observe its effect on conjugation.
  • Investigating potential mechanisms including CodY derepression, SOS response, and plasmid copy number (PCN).
  • Performing comparative transcriptomics between wild-type and mutant strains.

Main Results:

  • Clinical Rel mutations in Staphylococcus aureus significantly promote the donation, but not receipt, of diverse resistance plasmids.
  • Elevated (p)ppGpp levels, induced by Rel mutations or mupirocin, increase plasmid conjugal transfer frequency.
  • The observed increase in plasmid donation was independent of CodY derepression, SOS response, or altered PCN.
  • Comparative transcriptomics did not reveal clear plasmid- or host-derived mechanisms for the enhanced conjugation.

Conclusions:

  • Elevated (p)ppGpp, resulting from clinical Rel mutations or stringent response induction, enhances Staphylococcus aureus plasmid donation.
  • The mechanism linking (p)ppGpp to increased conjugation is complex and requires further investigation, as common regulatory pathways were ruled out.
  • The increasing prevalence of Rel mutations in clinical isolates is concerning due to their association with enhanced plasmid transfer and potential spread of antibiotic resistance.
Keywords:
(p)ppGppStaphylococcus aureusconjugationplasmidstringent response

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