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Isopedopeptins A-H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria

Nord, Christina and Bjerketorp, Joakim and Levenfors, Jolanta and Cao, Sha and Stromstedt, Adam A. and Guss, Bengt and Larsson, Rolf and Hughes, Diarmaid and Oberg, Bo and Broberg, Henrik (2020). Isopedopeptins A-H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria. ACS Chemical Biology. 15 , 2937-2944
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Abstract

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 mu g/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 mu g/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.

Authors/Creators:Nord, Christina and Bjerketorp, Joakim and Levenfors, Jolanta and Cao, Sha and Stromstedt, Adam A. and Guss, Bengt and Larsson, Rolf and Hughes, Diarmaid and Oberg, Bo and Broberg, Henrik
Title:Isopedopeptins A-H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria
Series Name/Journal:ACS Chemical Biology
Year of publishing :2020
Volume:15
Page range:2937-2944
Number of Pages:8
Publisher:AMER CHEMICAL SOC
ISSN:1554-8929
Language:English
Publication Type:Journal article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biochemistry and Molecular Biology
URN:NBN:urn:nbn:se:slu:epsilon-p-109745
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-109745
Additional ID:
Type of IDID
DOI10.1021/acschembio.0c00568
Web of Science (WoS)000592981100011
ID Code:21233
Faculty:NJ - Fakulteten för naturresurser och jordbruksvetenskap
VH - Faculty of Veterinary Medicine and Animal Science
Department:(NL, NJ) > Department of Molecular Sciences
(VH) > Department of Biomedical Science and Veterinary Public Health
Deposited By: SLUpub Connector
Deposited On:14 Jan 2021 16:23
Metadata Last Modified:15 Jan 2021 19:44

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