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⯵g/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⯵g/ml. Using a luciferase assay, the mechanism of action of G6 was shown to resemble the biocide chlorhexidine by targeting the bacterial cell membrane.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzamides/pharmacology , Biofilms/drug effects , Biological Products/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Sulfonamides/pharmacology , Anti-Bacterial Agents/chemistry , Benzamides/chemistry , Biological Products/chemistry , Drug Resistance, Multiple, Bacterial , Erythrocytes/drug effects , Hemolysis/drug effects , Humans , Microbial Sensitivity Tests , Seawater/chemistry , Sulfonamides/chemistryABSTRACT
A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5-2µg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE).E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL-CARBA producing multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds.
