Synthesis and antimicrobial activity of small cationic amphipathic aminobenzamide marine natural product mimics and evaluation of relevance against clinical isolates including ESBL-CARBA producing multi-resistant bacteria

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 22; pp. 5884 - 5894
• Main Authors: Igumnova, Elizaveta M., Mishchenko, Ekaterina, Haug, Tor, Blencke, Hans-Matti, Sollid, Johanna U. Ericson, Fredheim, Elizabeth G. Aarag, Lauksund, Silje, Stensvag, Klara, Strom, Morten B.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.11.2016
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biochemistry & Molecular Biology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial - drug effects; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Antimicrobial; Multi-resistant bacteria; ANTIBACTERIAL PEPTIDES; ESBL-CARBA; SUSCEPTIBILITY; Antibacterial; Aminobenzamides; Marine natural product mimics; BETA(2,2)-AMINO ACID; STAPHYLOCOCCUS; SPONGE; Peptidomimetics; PHARMACOPHORE; ALKALOIDS; ESBL–CARBA
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.09.046

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 0.5-2 mu g/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. (C) 2016 Elsevier Ltd. All rights reserved.