Isopedopeptins A H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top Priority Carbapenem Resistant Bacteria
Pedobacter cryoconitis strain UP508 was isolated from a soil sample using a mixture of ampicillin, kanamycin, and nalidixic acid for selection. UP508 was found to produce >30 unknown antibacterial peptides, of which eight, isopedopeptins A H (1 8) were isolated by bioassay guided fractionation and characterized with respect to structures and biological properties. Compounds 1 8 were all composed of nine amino acid residues and one 3 hydroxy fatty acid residue, and the structures were ring closed via an ester bond from the C terminal aspartic acid to the 3 hydroxy fatty acid. The differences between the peptides were the size and branching of the 3 hydroxy fatty acid and the presence of a valine or a 3 hydroxyvaline residue. The isopedopeptins mainly had activity against Gram negative bacteria, and isopedopeptin B (2) which had the best combination of antibacterial activity, in vitro cytotoxicity, and hemolytic properties, was selected for further studies against a larger panel of Gram negative bacteria. Isopedopeptin B was found to have good activity against strains of WHO top priority Gram negative bacteria, i.e. carbapenem resistant Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa, with minimal inhibitory concentrations (MIC) down to 1, 2, and 4 mg/mL, respectively. Furthermore, compound 2 had activity against colistin resistant strains of A. baumannii, E. coli, and Klebsiella pneumoniae, with a MIC down to 8, 2, and 4 mg/mL, respectively. Compound 6 was tested in an E. coli liposome system where it induced significant leakage, indicating membrane disruption as one mechanism involved in isopedopeptin antibacterial activity. Isopedopeptin B stands out as a promising candidate for further studies with the goal to develop a new antibiotic drug.
ACS chemical biology