Abstract
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 (1) and manool (2) extracted from Salvia tingitana were considered as potential QSI against methicillin-resistant Staphylococcus aureus. Only sclareol showed synergistic activity with clindamycin. The quantification of these compounds by LC–MS analysis in the organs and in the calli of S. tingitana 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 Salvia species, and pentacyclic triterpenoids, bearing a γ-lactone moiety, previously undescribed in Salvia. Docking simulations suggested that 1 and 2 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.
Highlights
Antibiotics are mandatory in controlling bacterial diseases both in the community and in healthcare settings
We reported the presence and the antimicrobial activity of sclareol and manool in the aerial parts Salvia tingitana Etl. [41], an aromatic woody-based perennial shrub originating from the Arabian region [42,43] that in the past was considered related to S. sclarea, while at present it is supposed a separate species [42,43]
Many of the virulence factors produced by pathogenic bacteria depend on quorum sensing, a microbial communication system
Summary
Antibiotics are mandatory in controlling bacterial diseases both in the community and in healthcare settings. They are one of the most critical medical interventions for surgical procedures, organ transplantations, and management of critically ill subjects, such as patients with cancer. Bacteria have evolved various strategies to avoid or resist the action of antibiotics. While some bacterial species are intrinsically resistant, other bacteria can acquire resistance by the exchange of mobile genetic elements, such as transposons, plasmids, and integrons. The newly acquired elements allow the bacterial cells to modify or destroy the antibiotic, pump the antibiotic out of the cell or decrease the uptake of the molecule, modify, or bypass the target of the antibiotic [1]. Bacteria can acquire more than one mechanism of antibiotic resistance. The use of antibiotics provides a selective pressure that causes the prevalence of multidrug resistance (MDR) strains and compromises the effectiveness of the drugs [2]
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