ArticlePLoS pathogens2010
Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection.
Article in PLoS pathogens, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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131 citing papers in PubMed, 210 citations in OpenAlex.
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- Structural Basis of pppGpp Binding to the N-Terminal Domain of the Bifunctional RelA/SpoT Homolog RelInternational journal of molecular sciences · 2026Article
- Clinical Rel mutations that increase basal (p)ppGpp promote conjugal transfer of staphylococcal resistance plasmids.Microbiology (Reading, England) · 2026Article
- Non-canonical stringent response signaling mediates antimicrobial fatty acid sensitivity inbioRxiv : the preprint server for biology · 2026Article
- Methicillin-Resistant Staphylococcus aureus Bacteremia Relapses Show Diverse Genomic Profiles but Convergence in Bacteremia-Associated Genes.The Journal of infectious diseases · 2025Article
- Determining the Importance of the Stringent Response for Methicillin-Resistant Staphylococcus aureus Virulence In Vivo.The Journal of infectious diseases · 2025Article
- Skin mycobiota-mediated antagonism against Staphylococcus aureus through a modified fatty acid.Current biology : CB · 2025Article
- Genomics for antimicrobial resistance-progress and future directions.Antimicrobial agents and chemotherapy · 2025Review
- Linezolid-Resistant Coagulase-Negative Staphylococci in a Tertiary Hospital: Molecular Epidemiology, Clinical Characteristics, and Outcomes.Infection & chemotherapy · 2025Article
- Antibiotic tolerance among clinical isolates: mechanisms, detection, prevalence, and significance.Clinical microbiology reviews · 2024Review
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- Phenotypic Variation inAntibiotics (Basel, Switzerland) · 2024Review
- C-terminal deletion of RelA protein is suggested as a possible cause of infective endocarditis recurrence withAntimicrobial agents and chemotherapy · 2024Article
- Bacterial heterogeneity and antibiotic persistence: bacterial mechanisms utilized in the host environment.Microbiology and molecular biology reviews : MMBR · 2023Review
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- ClinicalmSphere · 2023Article
- Detection, Identification and Diagnostic Characterization of the Staphylococcal Small Colony-Variant (SCV) Phenotype.Antibiotics (Basel, Switzerland) · 2023Review
- Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.Microbiology spectrum · 2023Article
- Article
- Review
71 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3', 5'-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens.
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