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Updated: Jan 8, 2026
Development and Assessment of Intracellular Infection Models for Staphylococcus aureus
Published on: January 17, 2025
Sub-minimum inhibitory concentrations of fosfomycin enhance Staphylococcus aureus virulence through the agr-PSM
Xueting Wan1, Yuan Wu1, Chenlin Zhang2
1Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
Objective:
Fosfomycin is increasingly used in combination therapies for multidrug-resistant bacterial infections. This study aimed to investigate the effect of sub-minimum inhibitory concentrations (sub-MICs) of fosfomycin on the virulence of Staphylococcus aureus to optimize therapeutic strategies.
Methods:
Hemolytic activity was assessed using disk diffusion and E-test assays on blood agar plates. The expression of virulence genes was quantified using reverse transcription polymerase chain reaction. Protein profiles were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The involvement of the accessory gene regulator (agr), α-hemolysin (hla), and phenol-soluble modulins (psm) was validated using mutant and complementation strains.
Results:
Sub-MICs of fosfomycin significantly enhanced hemolysis in both methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) strains. MALDI-TOF MS analysis revealed a marked increase in the production of phenol-soluble modulins (PSMs) in S. aureus harvested from fosfomycin sub-inhibitory zones. Genetic analyses confirmed that sub-MICs of fosfomycin induced hemolysis was abolished in the agr or psm mutants and restored upon psm complementation. Moreover, sub-MICs of other agents targeting cell wall synthesis, including β-lactams (ceftazidime) and glycopeptides (vancomycin), significantly enhanced S. aureus hemolysis.
Conclusion:
Sub-MICs of fosfomycin enhance S. aureus hemolysis by activating the agr-PSM pathway. These findings highlight the potential clinical risks associated with subtherapeutic fosfomycin exposure, which may exacerbate staphylococcal virulence during infection.
Insights
Sub-minimum inhibitory concentrations of fosfomycin increase Staphylococcus aureus virulence by enhancing hemolysis through the agr-PSM pathway. This suggests potential clinical risks with sub-optimal fosfomycin dosing in treating bacterial infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Fosfomycin is a key antibiotic for multidrug-resistant bacterial infections.
- Understanding sub-minimum inhibitory concentrations (sub-MICs) effects is crucial for optimizing therapy.
- Staphylococcus aureus virulence factors contribute to infection severity.
Purpose of the Study:
- To investigate the impact of fosfomycin sub-MICs on Staphylococcus aureus virulence.
- To elucidate the mechanisms underlying fosfomycin-induced virulence changes.
- To inform therapeutic strategies for S. aureus infections.
Main Methods:
- Assessed hemolytic activity using disk diffusion and E-test assays.
- Quantified virulence gene expression via reverse transcription polymerase chain reaction.
- Analyzed protein profiles using MALDI-TOF MS and validated gene involvement with mutant strains.
Main Results:
- Fosfomycin sub-MICs significantly enhanced hemolysis in both MSSA and MRSA strains.
- Increased production of phenol-soluble modulins (PSMs) was observed.
- Hemolysis enhancement was dependent on the accessory gene regulator (agr) and PSM pathway.
Conclusions:
- Fosfomycin sub-MICs activate the agr-PSM pathway, enhancing S. aureus hemolysis.
- Sub-optimal fosfomycin exposure may increase staphylococcal virulence.
- Clinical implications include potential risks of exacerbated infections with subtherapeutic dosing.
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