A combined metabolomics and biochemometrics approach for the rapid identification of antibacterial naphthyl derivatives from Guiera senegalensis leaves

: Staphylococcus epidermidis is a common component of the human skin microbiota, but it is also a major contributor to hospital-acquired infections, especially due to its ability to form biofilms. S. epidermidis strains often result multidrug-resistant (MDR) due to the presence of resistance genes to different classes of antibiotics. Clinically, MDR S. epidermidis complicates treatment of device-associated infections and sepsis, requiring advanced diagnostics and therapies to mitigate its impact in healthcare. Plant-derived natural products, due to their inherent chemical diversity, offer a promising avenue to address drug resistance, but modern technologies are essential to guide and accelerate the discovery pipeline. In this study, we present the identification of anti-bacterial naphthyl derivatives from Guiera senegalensis leaves, used in different African countries to treat infectious and chronic diseases. Our combined approach of untargeted LC-HRMS- and Molecular Networking-based metabolomics and NMR-based biochemometric analysis allowed both the comprehensive snapshot of the metabolome and the detection of key NMR-features responsible for the antibacterial activity exerted by the extract. NMR-fingerprint drove the chromatographic purification allowing the isolation of 7 naphthyl derivatives, including the new naphythyl-butenone guieranone C, and two unprecedented naphto-γ-pyrones, namely guierapyrones A and B. Isolated metabolites were tested for their anti-bacterial activity against oxacillin-suscptible S. epidermidis and oxacillin-resistant S. epidermidis unveiling guieranone A as a good candidate for fighting staphylococcal infections.