Labdane Diterpenoids from Salvia tingitana Etl. Synergize with Clindamycin against Methicillin-Resistant Staphylococcus aureus

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-11, Vol.26 (21), p.6681
• Main Authors: Iobbi, Valeria, Brun, Paola, Bernabé, Giulia, Dougué Kentsop, Roméo Arago, Donadio, Giuliana, Ruffoni, Barbara, Fossa, Paola, Bisio, Angela, De Tommasi, Nunziatina
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Bacteria; Biofilms; callus; Clindamycin; Clindamycin - pharmacology; Deoxyribonucleic acid; Diterpenes; DNA; Dose-Response Relationship, Drug; Drug resistance; Gene expression; Gram-positive bacteria; Kinases; manool; Metabolites; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Molecular Conformation; molecular docking; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Nosocomial infections; Organs; Pathogens; Pentacyclic triterpenoids; Phosphorylation; Phytochemicals - chemistry; Phytochemicals - pharmacology; Plant Extracts - chemistry; Plant Extracts - pharmacology; Quorum Sensing - drug effects; quorum sensing inhibitors; Roots; Salvia - chemistry; Salvia tingitana; sclareol; Staphylococcus aureus; Staphylococcus infections; Structure-Activity Relationship; Triterpenoids; Virulence; Virulence factors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26216681

Quorum-sensing (QS) is a regulatory mechanism in bacterial communication, important for pathogenesis control. The search for small molecules active as quorum-sensing inhibitors (QSI) that can synergize with antibiotics is considered a good strategy to counteract the problem of antibiotic resistance. Here the antimicrobial labdane diterpenoids sclareol ( ) and manool ( ) extracted from were considered as potential QSI against methicillin-resistant . Only sclareol showed synergistic activity with clindamycin. The quantification of these compounds by LC-MS analysis in the organs and in the calli of showed that sclareol is most abundant in the flower spikes and is produced by calli, while manool is the major labdane of the roots, and is abundant also in the leaves. Other metabolites of the roots were abietane diterpenoids, common in species, and pentacyclic triterpenoids, bearing a γ-lactone moiety, previously undescribed in . Docking simulations suggested that and bind to key residues, involved in direct interactions with DNA. They may prevent accessory gene regulator A (AgrA) binding to DNA or AgrA activation upon phosphorylation, to suppress virulence factor expression. The antimicrobial activity of these two compounds probably achieves preventing upregulation of the accessory gene regulator (agr)-regulated genes.