2-(2-Methyl-2-nitrovinyl)furan but Not Furvina Interfere with Staphylococcus aureus Agr Quorum-Sensing System and Potentiate the Action of Fusidic Acid against Biofilms

Abstract

Quorum sensing (QS) plays an essential role in the production of virulence factors, in biofilm formation and antimicrobial resistance. Consequently, inhibiting QS is being considered a promising target for antipathogenic/anti-virulence therapies. This study aims to screen 2-nitrovinylfuran derivatives structurally related to Furvina (a broad-spectrum antibiotic already used for therapeutic purposes) for their effects on QS and in biofilm prevention/control. Furvina and four 2-nitrovinylfuran derivatives (compounds 1–4) were tested to assess the ability to interfere with QS of Staphylococcus aureus using bioreporter strains (S. aureus ALC1742 and ALC1743). The activity of Furvina and the most promising quorum-sensing inhibitor (QSI) was evaluated in biofilm prevention and in biofilm control (combined with fusidic acid). The biofilms were further characterized in terms of biofilm mass, viability and membrane integrity. Compound 2 caused the most significant QS inhibition with reductions between 60% and 80%. Molecular docking simulations indicate that this compound interacts preferentially with the protein hydrophobic cleft in the LytTR domain of AgrA pocket. Metabolic inactivations of 40% for S. aureus ALC1742 and 20% for S. aureus ALC1743 were reached. A 24 h-old biofilm formed in the presence of the QSI increased the metabolic inactivation by fusidic acid to 80%, for both strains. The overall results highlight the effects of compound 2 as well as the potential of combining QSI with in-use antibiotics for the management of skin and soft tissues infections.

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

“…A careful literature overview highlighted some research studies based on the LytTR domain of the apo AgrA structure from S. aureus (PDB code 4G4K) performed by Leonard and co-workers [74], and a previous study (PDB code: 3BS1) [97], which reported the crystal structure of the DNA-binding domain of S. aureus AgrA complexed with a DNA pentadecamer duplex. On these bases we evaluated all the PDB structures in the PDB selecting 4G4K [74,76,[98][99][100]. Our approach was to evaluate the best resolution of this structure (1.52 Å) among the others, and the different conformations that the protein can assume depending to the presence or the absence of bound DNA.…”

Staphylococcus aureus biofilm: Formulation, regulatory, and emerging natural products-derived therapeutics

“…It involves multiple signal transduction pathways that regulate biofilm formation, virulence, motility, and sporulation [ 48 ]. In S. aureus , the research on QS system mainly focused on the accessory regulatory factor (Agr) system and LuxS/autoinducer-2 (AI-2) system [ [71] , [72] , [73] ].…”

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

“…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].…”

“…In addition, for strains and different concentrations of 63 and 62, most bacteria maintain membrane integrity (more than 70%), which is essential for the effective treatment of bacterial infections. Nevertheless, the synergistic mechanism between FA and 62 or 63 remains to be understood [72].…”