Abstract
Multidrug-resistant bacteria are a global health problem. One of the last-resort antibiotics against Gram-negative bacteria is the cyclic lipopeptide colistin, displaying a flexible linker with a fatty acid moiety. The aim of the present project was to investigate the effect on antimicrobial activity of introducing fatty acid moieties of different lengths and in different positions in a cyclic peptide, S3(B), containing a flexible linker. The lipidated analogues of S3(B) were synthesized by 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis. Following assembly of the linear peptide by Fmoc solid-phase peptide synthesis, on-resin head-to-tail cyclization and fatty acid acylation were performed. The antimicrobial activity was determined against the ESKAPE pathogens, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. Furthermore, hemolytic activity was determined against human erythrocytes. A total of 18 cyclic lipopeptides were synthesized and characterized. It was found that introduction of fatty acids in positions next to the flexible linker was more strongly linked to antimicrobial activity. The fatty acid length altered the overall hydrophobicity, which was the driving force for both high antimicrobial and hemolytic activity. Peptides became highly hemolytic when carbon-chain length exceeded 10 (i.e., C10), overlapping with the optimum for antimicrobial activity (i.e., C8–C12). The most promising candidate (C8)5 showed antimicrobial activity corresponding to that of S3(B), but with an improved hemolytic profile. Finally, (C8)5 was further investigated in a time-kill experiment.
Highlights
The inappropriate use of antibiotics has resulted in a global health crisis wherein multidrug-resistant bacteria often are encountered in healthcare-associated infections [1]
The antimicrobial activity was determined against the ESKAPE pathogens, while hemolytic activity was determined against human erythrocytes
Colistin and other cyclic lipopeptides naturally contain fatty acid tails that are essential for their antimicrobial activity
Summary
The inappropriate use of antibiotics has resulted in a global health crisis wherein multidrug-resistant bacteria often are encountered in healthcare-associated infections [1]. Worrying are the ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The treatment options are very limited, and the annual death toll caused by antimicrobial resistance is predicted to rise to 10 million by 2050 [3]. A recent survey of the preclinical antibacterial pipeline, ending May 2019, identified 407 preclinical trials, including direct-acting agents, antibodies and vaccines, phages and phage-related products, microbiota-modulating therapies, antivirulence approaches, antimicrobial potentiators, repurposed drugs, and immunomodulatory molecules [4]. Siderophore-antibiotic conjugates such as cefiderocol constitute an interesting new class of antibacterial agents [5]
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