Lipidation of temporin‐1ceb derivatives as a tool for activity improvement, pros and cons of the approach

Abstract

The alarming raise of multi‐drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicro-bial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhance-ment of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR‐PEG‐DK5, derivatized at their N‐terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved an-timicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre‐formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5‐DK5, C12‐DK5 and C12‐CAR‐PEG‐DK5) were also potent against multi‐drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity.