Biotope-dependent High Level Resistance to Reactive Oxygen Species, Antibiotic Tolerance, and Virulence of Staphylococcus aureus

Vincent Léguillier; Karine Gloux; Majd Khalife; Rochelle D’Mello; Zoran Minić; Milica Sentić; Marta Catto; Marisa Manzano; Christine Péchoux; Sandrine Truchet; Philippe Gaudu; Christina Nielsen‐LeRoux; Brahim Heddi; Alexandra Gruss; Jasmina Vidić

doi:10.1101/2025.10.31.685911

MicrobiologybioRxivOct 31, 2025

Preprint

Biotope-dependent High Level Resistance to Reactive Oxygen Species, Antibiotic Tolerance, and Virulence of Staphylococcus aureus

Vincent Léguillier iD, Karine Gloux iD, Majd Khalife iD, Rochelle D’Mello iD, Zoran Minić iD, Milica Sentić iD, Marta Catto, Marisa Manzano iD, Christine Péchoux iD, Sandrine Truchet iD, Philippe Gaudu iD, Christina Nielsen‐LeRoux iD, Brahim Heddi iD, Alexandra Gruss iD, Jasmina Vidić iD

Abstract

The human and livestock pathogen Staphylococcus aureus poses a major clinical challenge due to antibiotic treatment failure. Its resilience is mainly attributed to antibiotic resistance and tolerance mechanisms related to persistence. Here we investigate how two infection-relevant biotopes, milk and serum, shape S. aureus pathogenic properties and capacity to withstand environmental stresses. Milk-versus serum-adapted bacteria show gross differences in envelope physical properties, membrane fatty acid composition and rigidity, and pigment production, and display distinct proteomic profiles. Compared to serum, milk adaptation of S. aureus confers extreme resistance to ROS damage, pronounced antimicrobial tolerance, and accelerated killing in an insect infection model. High level S. aureus pigmentation in whole milk is stimulated by milk lipids, and is responsible for high ROS resistance. The remarkable robustness of S. aureus in a milk biotope may signal the need to adjust antibiotic regimens when treating mastitis infections in humans and livestock.

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