Investigation of tetrasubstituted heterocycles reveals hydantoins as a promising scaffold for development of novel antimicrobials with membranolytic properties

Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemolytic activity of the com-pounds, and the hydantoin scaffold was identified as a promising template for drug lead development. Subse-quently, a total of 20 hydantoin derivatives were studied for their antimicrobial potency and haemolytic activity. We found 19 of these derivatives to have very low haemolytic toxicity and identified three lead structures, 2dA, 6cG, and 6dG with very promising broad-spectrum antimicrobial activity. Lead structure 6dG displayed mini-mum inhibitory concentration (MIC) values as low as 1 mu g/mL against Gram-positive bacteria and 4-16 mu g/mL against Gram-negative bacteria. Initial mode of action (MoA) studies performed on the amine derivative 6cG, utilizing a luciferase-based biosensor assay, suggested a strong membrane disrupting effect on the outer and inner membrane of Escherichia coli. Our findings show that the physical properties and structural arrangement induced by the heterocyclic scaffolds are important factors in the design of AMP mimics.

Automated summary

Mimics of antimicrobial peptides (AMPs) have been studied. Heterocyclic scaffolds have a strong influence on the haemolytic activity of compounds. The hydantoin scaffold is identified as a promising template for drug lead development. Among the studied hydantoin derivatives, three lead structures, 2dA, 6cG, and 6dG, show very promising broad-spectrum antimicrobial activity.