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Bioassay-guided fractionation of the liquid culture broth of Pseudomonas sp. MF381-IODS yielded two new antimicrobial substances, identified as (2E,4E,6E)-9-[((2S,3R)-3-hydroxy-4-{[(3E,5E,7RS)-7-hydroxy-4-methylhexadeca-3,5-dienoyl]amino}-2-methylbutanoyl)amino]nona-2,4,6-trienoic acid and the tetradeca equivalent, named pseudotrienic acids A (1) and B (2), respectively. The compounds are prone to lactone formation, and their structures suggest them to be derived from ring opening of a macrolide. Pseudotrienic acids A and B inhibited growth of Staphylococcus aureus (MIC 70 microg/mL) and Pseudomonas syringae pv. syringae (MIC 70 microg/mL). Two known antimicrobial compounds, the polyketide 2,3-deepoxy-2,3-didehydrorhizoxin (3) and the tryptophan-derived pyrrolnitrin (4), were also identified.

Five new (5-9) and four known (1-4) kutznerides were isolated from the actinomycete Kutzneria sp. 744. Compounds 1-9 all consisted of a cyclohexadepsipeptide core with the general structure 2-(1-methylcyclopropyl)-D-glycine-(2S,3aR,8aS)-6,7-dichloro-3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid-3-hydroxy-D-glutamic acid-O-methyl-L-serine-L-piperazic acid-(S)-2-hydroxy-3,3-dimethylbutyric acid. Compounds 5, 6, and 8 contained erythro-3-hydroxy-D-glutamic acid, whereas 7 and 9 contained the threo isomer and the hydroxy acid was present as (S)-2-hydroxy-3-methylbutyric acid in 5 and 7. The piperazic acid was C-5-N unsaturated and 4-hydroxylated in 6, 4-chlorinated in 8, and C-5-N unsaturated in 9. Minimal inhibitory concentrations for bacteria were found down to 6 microM (Staphylococcus aureus and Erwinia carotovora) and for fungi down to 70 microM (Fusarium culmorum). The trichlorinated 2 and 8 showed the highest antimicrobial activity, whereas 6, with a hydroxylated piperazic acid unit, did not show any inhibition of the pathogens at 230 microM.

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 μg/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 μg/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.