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An anti-adhesive compound modulating the production of Staphylococcus aureus cell wall-anchored proteins

ABSTRACT: Staphylococcus aureus is the leading global cause of death associated with antimicrobial resistance, driven by its ability to colonize the human nasal cavity and adhere to the keratinized skin epithelium. These colonizers are the primary source of subsequent infections, underscoring the need for decolonization strategies. Using a high-throughput whole cell-based S. aureus adhesion screen, we identified a naturally occurring polyunsaturated branched-chain fatty acid, geranylgeranoic acid (GGA), that inhibits S. aureus adhesion to keratin at concentrations that do not affect cell growth. Mechanistic characterization demonstrated that GGA is a broad-spectrum anti-adhesive compound, inhibiting S. aureus adhesion to keratin, fibronectin, fibrinogen, and immunoglobulins. Structure-activity studies revealed that the carboxylic acid moiety and the presence of one or more double bonds in the carbon chain are key to activity, with various unsaturated fatty acids, including host-derived compounds, showing potent anti-adhesive properties. GGA was found to modulate the production of several S. aureus cell wall-anchored (CWA) proteins; for the fibronectin-binding proteins, this was linked to inhibition of the SaeRS two-component system, impairing S. aureus invasion of endothelial cells. In summary, GGA is a potent, naturally occurring anti-adhesive compound that modulates the production of CWA proteins in S. aureus. Our findings further emphasize the complex role of unsaturated fatty acids in host-pathogen interactions and their potential as S. aureus antivirulence agents.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE290916 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Systematic analyses of the temporal dynamics of transcriptomes and chromatin landscapes of macrophages during timecourse of TLR4-mediated inflammatory response. As a multifunctional effector cell, macrophages play pivotal roles in both the induction and resolution components of varied inflammatory processes. During the course of an inflammation response, macrophages engage in a homeostatic program characterized by tightly coordinated modulation of temporal outputs of both lipid metabolism and inflammation. We demonstrate inversely biphasic temporal dynamics of specific fatty acid metabolic and inflammatory gene expression profiles, associated with concordant temporal reprogramming of macrophage fatty acid profiles. In part, the late phase of the macrophage inflammatory response is characterized by tailoring of fatty acid related gene expressions, facilitating both significant induction of anti-inflammatory unsaturated fatty acid production and associated resolution of inflammation. We demonstrate the biphasic temporal dynamics of macrophage inflammation, specifically anti-inflammatory omega-3 and omega-9 unsaturated fatty acid levels, are transcriptionally driven genome-wide by an unexpected shift from an LXR to SREBP1-dominant regulatory program in the late phase inflammatory response. Collectively, our findings reveal a novel Srebp1-driven mechanism allowing the intimate inverse temporal relationship between the transcriptional regulation of inflammatory and fatty acid metabolic outputs; whereby modulation key transcriptional regulators (LXR, SREBP1 and NF-kB) of these pathways coordinate appropriate temporal tailoring of local enhancer associated reprogramming and eventual pathway regulatory interactions, during the course of TLR4-dependent inflammatory response in macrophages. This specific Srebp-driven, temporal reprogramming of macrophage fatty acid metabolism, characterized by late phase induction of anti-inflammatory unsaturated fatty acid production, is necessary for appropriate resolution of inflammation. Thus, this study suggests that selective reprogramming of macrophage lipid metabolism can serve as a viable therapeutic intervention aimed at ameliorating chronic inflammation and varied metabolic syndrome associated states.

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An anti-adhesive compound modulating the production of Staphylococcus aureus cell wall-anchored proteins

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