Abstract
In the era of antibiotic resistance, there is an urgent need for efficient antibiotic therapies to fight bacterial infections. Cationic antimicrobial peptides (CAMP) are promising lead compounds given their membrane-targeted mechanism of action, and high affinity towards the anionic composition of bacterial membranes. We present a new CAMP, W-BP100, derived from the highly active BP100, holding an additional tryptophan at the N-terminus. W-BP100 showed a broader antibacterial activity, demonstrating a potent activity against Gram-positive strains. Revealing a high partition constant towards anionic over zwitterionic large unilamellar vesicles and inducing membrane saturation at a high peptide/lipid ratio, W-BP100 has a preferential location for hydrophobic environments. Contrary to BP100, almost no aggregation of anionic vesicles is observed around saturation conditions and at higher concentrations no aggregation is observed. With these results, it is possible to state that with the incorporation of a single tryptophan to the N-terminus, a highly active peptide was obtained due to the π–electron system of tryptophan, resulting in negatively charged clouds, that participate in cation–π interactions with lysine residues. Furthermore, we propose that W-BP100 action can be achieved by electrostatic interactions followed by peptide translocation.
Highlights
Antibiotic resistance is recognized by the World Health Organization (WHO) as a global public health threat
The overuse and misuse of antibiotics has led to the increase of multidrug-resistant (MDR) bacteria belonging to the “ESKAPE” pathogens group, comprising the strains Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp, which are listed in the 2017 WHO priority pathogen list, and are most commonly associated to nosocomial infections [1]
The lack of alternatives to clinically available antibiotics led to an urgent race towards the discovery of new and effective antimicrobial agents capable of surpassing bacterial resistance
Summary
Antibiotic resistance is recognized by the World Health Organization (WHO) as a global public health threat. Cationic antimicrobial peptides (CAMP) are part of the innate immune system of many organisms including humans, bacteria, plants, insects, and amphibians [3,4] They are a promising alternative to antibiotics since most of them target and permeabilize the bacterial membranes, making them less prone to elicit resistance as described for conventional antibiotics [5]. Both cationic and amphipathic properties of CAMP are key on their mechanism of action (MOA), promoting their interaction and incorporation into the negatively charged bacterial membranes by means of electrostatic and/or hydrophobic interactions [5] Their attractive properties and antimicrobial activity against bacteria, viruses, and fungi have place CAMP in the research pipeline for the discovery of new antibacterial agents, with many being selected for phase II–IV of clinical trials, mostly for topical application [6]
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