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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, antimicrobial 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 enhancement 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 antimicrobial 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.

SUBMITTER: Kosikowska-Adamus P

PROVIDER: S-EPMC8269107 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Macroalgae stand out for their high content of dietary fiber (30-75%) that include soluble, sulfated (fucoidan, agaran, carrageenan, and ulvan) and non-sulfated (laminaran and alginate) polysaccharides. Many studies indicate that these compounds exert varied biological activities and health-promoting effects and for this reason, there is a growing interest for using them in food products. The aim of this review was to critically evaluate prebiotic properties of algal polysaccharides, i.e., their ability to exert biological activities by modulating the composition and/or diversity of gut microbiota (GM). Pre-clinical studies show that the non-sulfated alginate and laminaran are well-fermented by GM, promoting the formation of short chain fatty acids (SCFAs) including butyrate, and preventing that of harmful putrefactive compounds (NH3, phenol, p-cresol, indole and H2S). Alginate increases Bacteroides, Bifidobacterium, and Lactobacillus species while laminaran mostly stimulates Bacteroides sp. Results with sulfated polysaccharides are more questionable. Agarans are poorly fermentable but agarose-oligosaccharides exhibit an interesting prebiotic potential, increasing butyrate-producing bacteria and SCFAs. Though carrageenan-oligosaccharides are also fermented, their use is currently limited due to safety concerns. Regarding fucoidan, only one study reports SCFAs production, suggesting that it is poorly fermented. Its effect on GM does not indicate a clear pattern, making difficult to conclude whether it is beneficial or not. Notably, fucoidan impact on H2S production has not been evaluated, though some studies report it increases sulfate-reducing bacteria. Ulvan is badly fermented by GM and some studies show that part of its sulfate is dissimilated to H2S, which could affect colonic mitochondrial function. Accordingly, these results support the use of laminaran, alginate and agaro-oligosaccharides as prebiotics while more studies are necessary regarding that of fucoidan, carrageenan and ulvan. However, the realization of clinical trials is necessary to confirm such prebiotic properties in humans.

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Lipidation of Temporin-1CEb Derivatives as a Tool for Activity Improvement, Pros and Cons of the Approach.

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