title: Structure, toxicity and antibiotic activity of gramicidin S and derivatives.
abstract: Development of new antibiotics is declining whereas antibiotic resistance is rising, heralding a post-antibiotic era. Antimicrobial peptides such as gramicidin S (GS), exclusively topically used due to its hemolytic side-effect, could still be interesting as therapeutic compounds. By modifying the amino-acid composition of GS, we synthesized GS analogues. We now show that derivative VK7 has a lower MIC (7.8-31.2 μg/ml, median 15.6 μg/ml) against strains of multi-drug resistant (MDR) Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa than GS has (3.9-62.5 μg/ml, median 31.3 μg/ml). Low MICs for both VK7 and GS were observed for Staphylococcus aureus and Enterococcus faecium. VK7 showed reduced haemolysis and less lactate dehydrogenase release. All compounds were fully bactericidal at MIC values. Modification of GS enables production of novel derivatives potentially useful for systemic treatment of human infections.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. jasperswierstra@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Swierstra
authors.affiliation: Faculty of Science, Bio-Organic Synthesis, Gorlaeus Laboratories, Leiden Institute of Chemistry, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Kapoerchan
authors.affiliation: Faculty of Science, Bio-Organic Synthesis, Gorlaeus Laboratories, Leiden Institute of Chemistry, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Knijnenburg
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.|bioMérieux, R&D Microbiology, 3 Route de Port Michaud, La Balme-Les-Grottes, 38390, France.
authors.forename: A
authors.initials: A
authors.lastname: van Belkum
authors.affiliation: Faculty of Science, Bio-Organic Synthesis, Gorlaeus Laboratories, Leiden Institute of Chemistry, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Overhand
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006096:Gramicidin / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006461:Hemolysis; D006801:Humans; D045022:Lactate Dehydrogenases / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin; D045022:Lactate Dehydrogenases