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.

Diana Oliveira,Anabela Borges,Zenaida Rodríguez Negrín,Manuel Simões,Simona Distinto,Fernanda Borges,Reinaldo Molina Ruiz

doi:10.3390/ijms22020613

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.

Highlights

Staphylococcus aureus is an opportunistic pathogen widely associated with skin colonization and biofilm-related infections [1]
This study aims to screen 2-nitrovinylfuran derivatives structurally related to Furvina for their effects on Quorum sensing (QS) and in biofilm prevention/control
The inappropriate use of antibiotics as well as the natural evolution and adaptation of microorganisms has led to an increase of bacterial resistance to the most commonly administered therapeutic drugs [31,32]

Summary

Introduction

Staphylococcus aureus is an opportunistic pathogen widely associated with skin colonization and biofilm-related infections [1]. Due to the widespread use of topical antibiotics, mupirocin and fusidic acid, there is an increase in bacterial resistance [2]. Such phenomenon is closely associated with ability of bacteria to adapt to the environment they inhabit, either by changing their phenotype or their metabolism [3]. Bacteria possess a gene regulation mechanism known as quorum sensing (QS) that is used to orchestrate group behavior [4]. This mechanism is based on intercellular communication and occurs only when bacteria reach a threshold cell density. Contributing for bacterial pathogenicity [9,10]

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