Abstract
Antimicrobial peptides (AMPs) are excellent candidates to fight multi-resistant pathogens worldwide and are considered promising bio-preservatives to control microbial spoilage through food processing. To date, designing de novo AMPs with high therapeutic indexes, low-cost synthesis, high resistance, and bioavailability, remains a challenge. In this study, a novel decapeptide, named RiLK1, was rationally designed starting from the sequence of the previously characterized AMP 1018-K6, with the aim of developing short peptides, and promoting higher selectivity over mammalian cells, antibacterial activity, and structural resistance under different salt, pH, and temperature conditions. Interestingly, RiLK1 displayed a broad-spectrum of bactericidal activity against Gram-positive and Gram-negative bacteria, including multidrug resistant clinical isolates of Salmonella species, with Minimal Bactericidal Concentration (MBC) values in low micromolar range, and it was effective even against two fungal pathogens with no evidence of cytotoxicity on human keratinocytes and fibroblasts. Moreover, RiLK1-activated polypropylene films were revealed to efficiently prevent the growth of microbial spoilage, possibly improving the shelf life of fresh food products. These results suggested that de novo designed peptide RiLK1 could be the first candidate for the development of a promising class of decameric and multitask antimicrobial agents to overcome drug-resistance phenomena.
Highlights
The alarming development and rapid spread of antibiotic resistance among pathogenic microbes has emerged as the major cause of the reduced effectiveness of antimicrobial therapies, thereby representing a huge challenge for modern medicine and a very large public health threat [1,2]
antimicrobial peptides (AMPs) are effective against a diverse spectrum of organisms, such as Gram-positive and Gram-negative bacteria, as well as fungi and viruses, and their nonspecific mode of action significantly prevents resistance phenomena, as it is metabolically costly for most microbes to mutate or repair membrane components [8,9]
Antimicrobial peptides based on naturally occurring AMPs are amphiphilic agents with broad-spectrum antimicrobial activities and able to kill pathogens mainly by mechanically damaging the integrity of the bacterial membrane [5,6]
Summary
The alarming development and rapid spread of antibiotic resistance among pathogenic microbes has emerged as the major cause of the reduced effectiveness of antimicrobial therapies, thereby representing a huge challenge for modern medicine and a very large public health threat [1,2]. Antimicrobial peptides (AMPs), evolutionary ancient factors of the innate immune system, have attracted increased attention as novel antimicrobials to replace or supplement conventional antibiotics for the control of infections sustained by pathogens, due to the broad-spectrum activity, and unique membrane-action mechanism of these compounds that is mainly related to their amphipathic properties [5,6]. A rational in silico analysis to design novel AMPs with optimized structural properties, and/or to project chemical modifications of existing ones, represent a promising strategy to overcome the limitations of native peptides and improve the therapeutic use of AMPs in drug-resistant bacteria or fungi treatments [11]. This approach allows to get molecules with improved antimicrobial efficacy, broader spectrum of action, and reduced costs of production, correspondingly [12,13]
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