Sub-minimum inhibitory concentrations of fosfomycin enhance Staphylococcus aureus virulence through the agr-PSM pathway

  • Microb Pathog. 2026 Jan:210:108138. doi: 10.1016/j.micpath.2025.108138.
Xueting Wan  1 ,  Yuan Wu  1 ,  Chenlin Zhang  2 ,  Zhiqiang Yu  3 ,  Zhen Luo  4
Affiliations
  • 1. Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
  • 2. Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China.
  • 3. Department of Laboratory Medicine, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, China. Electronic address: [email protected].
  • 4. Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: [email protected].
PMID: 41429753 DOI: 10.1016/j.micpath.2025.108138
Abstract

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.

Keywords
Fosfomycin; Hemolysis; Phenol-soluble modulin; Staphylococcus aureus; agr.
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