Multi-omics reveals the sesquiterpenoid (−)-globulol induces lethal autolysis in Staphylococcus aureus through coordinated disruption of cell wall synthesis and metabolite homeostasis

Abstract

Staphylococcus aureus ( S. aureus ) remains one of the major causes of persistent infections in livestock. The escalating threat of S. aureus infections, compounded by widespread antibiotic resistance, drives an urgent search for innovative antibacterial compounds. Sesquiterpenoids like (−)-globulol represent a promising source of novel bioactivity. In vitro experiments showed that (−)-globulol exhibited a minimum inhibitory concentration (MIC) of 7.81 µg/mL against S. aureus and significantly inhibited bacterial growth. In the mouse pneumonia model, in vivo studies show that (−)-globulol (25 mg/kg) increased the survival rate of infected mice, reduced the degree of inflammation in the lungs, significantly reduced bacterial load, and significantly alleviated pulmonary edema. Integrated proteomic and metabolomic analyses revealed that (−)-globulol coordinately disrupted bacterial amino acid metabolism (e.g., arginine and glutamate metabolism), ABC transporter pathway, and cell wall synthesis networks, thereby exerting multi-target antibacterial effects. Transmission electron microscopy revealed that this compound caused structural damage to the bacterial cell wall, including roughness, blurred outlines, and feathery edges, while promoting whole-cell and cell wall autolysis. Further mechanistic studies demonstrated that (−)-globulol reduced the O-acetylation level and cross-linking density of peptidoglycan (PG), thereby potentially altering its chemical modification status and enhancing its susceptibility to hydrolytic enzymes. In addition, (−)-globulol specifically upregulated the gene and protein expression of key autolysins (e.g., LytM), and enhanced their hydrolytic activity against pentaglycine cross-bridges. This study demonstrates that (−)-globulol exerts potent antibacterial activity by remodeling the metabolic network and cell wall homeostasis of S. aureus , providing new insights for developing multi-target antibacterial agents targeting the bacterial cell wall.