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

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.

Research Progress on the Combination of Quorum-Sensing Inhibitors and Antibiotics against Bacterial Resistance

“…The results showed that 65 has a synergistic effect with CD (FICI was 0.45); the study also found that 65 can bind to the AgrA protein, which may disable AgrA signal receptors. Once the AgrA signal receptor is disabled, it inhibits the release of virulence factors of S. aureus, which also shows that 65 binding to CD can effectively inhibit the QS system in bacteria and treat bacterial infection [74].…”

“…Unlike the mainstream antibiotics described above, relatively few studies have been conducted on the combination of fusidic acid (FA) or clindamycin (CD) with QSIs. However, this drug combination provides a new direction for the fight against S. aureus or its resistant strains [72][73][74].…”

The bioactivities of sclareol: A mini review

“…Importantly, the wide-spectrum effect against filoviruses of SCL has been proposed, especially, SCL was considered as Ebola virus (EBOV) entry inhibitor by interfering the viral fusion process (EC 50 = 2.4 μm) ( Chen Q. et al, 2020 ). In antibiotic resistance, SCL performed synergistic effect with clindamycin against Methicillin-resistant Staphylococcus aureus ( Iobbi et al, 2021 ) . SCL also exerted antifungal synergies with Curcumin towards various fungus, including Candida albicans , C. glabrata , Aspergillus fumigatus ( Augostine and Avery, 2022 ).…”

Recent advances on the regulation of bacterial biofilm formation by herbal medicines

“…The labdane diterpenoids sclareol and manool from Salvia tingitana are considered potential QSIs against methicillin-resistant S. aureus (MRSA). They can inhibit MRSA biofilm formation and virulence factor expression by prevention of the activation of AgrA upon binding or phosphorylation of the helper gene regulator AgrA to DNA ( Iobbi et al, 2021 ). Guo et al investigated the effect of andrographolide, the main active ingredient of Andrographis paniculata , on the pathogenies of APEC O78.…”