Abstract
The discovery of new anti-infective compounds is stagnating and multi-resistant bacteria continue to emerge, threatening to end the “antibiotic era”. Antimicrobial peptides (AMPs) and lipo-peptides such as daptomycin offer themselves as a new potential class of antibiotics; however, further optimization is needed if AMPs are to find broad use as antibiotics. In the present work, eight analogues of mastoparan-X (MPX) were investigated, having side chain modifications in position 1, 8 and 14 to modulate peptide hydrophobicity. The self-association properties of the peptides were characterized, and the peptide-membrane interactions in model membranes were compared with the bactericidal and haemolytic properties. Alanine substitution at position 1 and 14 resulted in higher target selectivity (red blood cells versus bacteria), but also decreased bactericidal potency. For these analogues, the gain in target selectivity correlated to biophysical parameters showing an increased effective charge and reduction in the partitioning coefficient for membrane insertion. Introduction of an unnatural amino acid, with an octyl side chain by amino acid substitution, at positions 1, 8 and 14 resulted in increased bactericidal potency at the expense of radically reduced membrane target selectivity. Overall, optimized membrane selectivity or bactericidal potency was achieved by changes in side chain hydrophobicity of MPX. However, enhanced potency was achieved at the expense of selectivity and vice versa in all cases.
Highlights
Antibiotics are one of the most important inventions in biomedical research, yearly saving the lives of millions of people
For Adec8, which is alkylated at the midpoint of the peptide sequence, the peptide may serve as a bulky headgroup on top of the C8 acyl chain, which could cause formation of different structures than the ones formed by the linear molecular constructs like OAMPX, Adec1 and Adec14
The Adec1, Adec8, Adec14 and OAMPX analogues investigated in the present work have equivalent cmc values as the C14 AKK analogue reflecting the larger hydrophobicity of MPX compared to AKK
Summary
Antibiotics are one of the most important inventions in biomedical research, yearly saving the lives of millions of people. Antimicrobial peptides (AMPs) offer themselves as potential drugs for treating bacterial, fungal, and viral infections, and as a new class of antibiotics. In higher eukaryotes such as plants and vertebrates, antimicrobial peptides are a natural part of the innate immune system, and serve as the first line of defence against infections [3]. In humans, these peptides are primarily located on skin and on mucosal surfaces, where they protect e.g. the oral tract, lungs, and intestines against bacterial and fungal infections. These small molecule drugs have been optimized though evolution to combat invading microorganisms, and several have been shown to exhibit activity towards various bacteria, viruses, fungi, and parasites [5]
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