Amphipathic sulfonamidobenzamides mimicking small antimicrobial marine natural products; investigation of antibacterial and anti-biofilm activity against antibiotic resistant clinical isolates

Abstract

There is an urgent need for novel antimicrobial agents to address the threat of bacterial resistance to modern society. We have used a structural motif found in antimicrobial marine hit compounds as a basis for synthesizing a library of antimicrobial sulfonamidobenzamide lead compounds. Potent in vitro antimicrobial activity against clinically relevant bacterial strains was demonstrated for two compounds, G6 and J18, with minimal inhibitory concentrations (MIC) of 4-16 μg/ml against clinical methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). The two compounds G6 and J18, together with several other compounds of this library, also caused ≥90% eradication of pre-established biofilm of methicillin-resistant S. epidermidis (MRSE) at 40 μg/ml. Using a luciferase assay, the mechanism of action of G6 was shown to resemble the biocide chlorhexidine by targeting the bacterial cell membrane.

Keywords: Antibacterial; Antimicrobial; ESBL – CARBA; Marine natural product mimics; Multi-resistant bacteria; Peptidomimetics; Sulfonamidobenzamides.