N‑Lipidated Peptide Dimers: Effective Antibacterial Agents against Gram-Negative Pathogens through Lipopolysaccharide Permeabilization

Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interac...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2015-08, Vol.58 (16), p.6533-6548
Main Authors: Koh, Jun-Jie, Lin, Huifen, Caroline, Vonny, Chew, Yu Siang, Pang, Li Mei, Aung, Thet Tun, Li, Jianguo, Lakshminarayanan, Rajamani, Tan, Donald T. H, Verma, Chandra, Tan, Ai Ling, Beuerman, Roger W, Liu, Shouping
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - toxicity
Carbapenems - pharmacology
Cell Membrane - drug effects
Cell Survival
Drug Resistance, Bacterial
Enterobacteriaceae - drug effects
Fatty Acids - chemistry
Female
Fibroblasts - drug effects
Gram-Negative Bacteria - drug effects
Hemolysis - drug effects
Humans
In Vitro Techniques
L-Lactate Dehydrogenase - metabolism
Lipopeptides - chemical synthesis
Lipopeptides - pharmacology
Lipopeptides - toxicity
Lipopolysaccharides - metabolism
Male
Mice
Microbial Sensitivity Tests
Permeability
Rabbits
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interaction with lipopolysaccharide (LPS) and facilitate the permeabilization of the LPS barrier, thereby improving potency against Gram-negative pathogens. We systematically designed a series of N-lipidated peptide dimers that are active against Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). The optimized lipid length was 6–10 carbons. At these lipid lengths, the N-lipidated peptide dimers exhibited strong LPS permeabilization. Compound 23 exhibited synergy with select antibiotics in most of the combinations tested. 23 and 32 also displayed rapid bactericidal activity. Importantly, 23 and 32 were nonhemolytic at 10 mg/mL, with no cellular or in vivo toxicity. These characteristics suggest that these compounds can overcome the limitations of current Gram-negative-targeted antimicrobials such as polymyxin B.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00628