Structure-activity relationships in ultrashort cationic lipopeptides: the effects of amino acid ring constraint on antibacterial activity.

Abstract:

:Taking a minimalistic approach in efforts to lower the cost for the development of new synthetic antimicrobial peptides, ultrashort cationic lipopeptides were designed to mimic the amphiphilic nature crucial for their activity but with only a very short peptide sequence ligated to a lipidic acid. Nine ultrashort cationic lipopeptides were prepared to study the effects of ring constraint in the amino acid side chain of the peptide component. USCL-PCat1, consisting of only four L-4R-aminoproline residues and acylated with palmitic acid at the N-terminus, was found to populate a polyproline II helical secondary conformation that is stable to different pHs and temperatures using circular dichroism. The synthesized lipopeptides were found to have a micellar structure in water using negative staining transmission electron microscopy. We found that constraining the side chain of the amino acid component is not beneficial to the antimicrobial activity. USCL-Dab1, USCL-Dab3 and USCL-K1 showed promising activity against a panel of laboratory reference and clinically isolated Gram-positive and Gram-negative bacterial strains, some of which are multidrug resistant. No appreciable cytotoxicity against human monocytic THP-1 cells was observed up to concentrations of 20-40 µM for all synthesized compounds. Moreover, all USCLs did not induce the production of either pro-inflammatory cytokines or chemokines up to 40 µM.

journal_name

Amino Acids

journal_title

Amino acids

authors

Domalaon R,Yang X,O'Neil J,Zhanel GG,Mookherjee N,Schweizer F

doi

10.1007/s00726-014-1806-z

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

2517-30

issue

11

eissn

0939-4451

issn

1438-2199

journal_volume

46

pub_type

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