Novel nitric oxide donors as antimicrobial agents

Abstract

The emergence of antibiotic resistance has highlighted the need to identify new antimicrobials that target bacterial pathogenicity without bactericidal effects. One such strategy exploits the inhibition of bacterial quorum sensing (QS) pathways, which are responsible for the expression of pathogenicity traits. Nitric oxide (NO) an endogenous cell mediator is also of major interest as an antimicrobial due to its ability to disperse and inhibit microbial biofilms via non-biocidal mechanism of action. This project focuses on the design and synthesis of novel dual action NO donors based on quorum sensing inhibitors as antimicrobials. Acylated homoserine lactone (AHL) based QS inhibitors mimicking the natural autoinducers were conjugated with NO donors such as nitrates, diazeniumdiolates and S-nitrosothiol to develop novel dual action NO donors. Fimbrolides, a class of halogenated marine natural products isolated from Delisea species, are known for their potent bacterial QS inhibitory activity. A wide range of novel fimbrolide derivatives containing NO donor groups has been synthesized and evaluated for their antimicrobial properties. An unusual and hitherto-unknown conversion of the halogenated furanones to a thiophene skeleton was observed during preparation of thiol fimbrolides. A new class of fimbrolide disulfide compounds with no literature precedent was discovered. Dihydropyrrolone based QS inhibitors were also conjugated with nitrates to develop novel hybrids. Novel indole based C-diazeniumdiolates and high load NO donors were also synthesized. Crystal structure analyses of selected molecules revealed interesting intermolecular halogen bonding and carbonyl-carbonyl dipolar interactions. Molecular docking studies with LasR protein were also conducted to understand the influence of structural modification on the binding properties of the molecules. Docking studies also displayed possibilities of halogen bonding interactions in the ligand binding site. The newly synthesized compounds were analyzed for their QS inhibitory efficacy and NO release properties in in-vitro assays. Their efficacy in biofilms inhibition and dispersion was also evaluated. The novel NO hybrid compounds showed significant biological activity which highlighted their potential for further development.