Abstract
Currently, the majority of antibiotics in clinical use have broad activity spectra, killing pathogenic and beneficial microorganisms indiscriminately. The disruption of the ecological balance of normal flora often results in secondary infections or other antibiotic-associated complications. Therefore, targeted antimicrobial therapies capable of specifically eliminating pathogenic bacteria while retaining the protective benefits of a normal microflora would be advantageous. In this study, we successfully constructed a series of Enterococcus faecalis-targeted antimicrobial peptides from wide-spectrum antimicrobial peptide precursors. These peptides are designed based on fusion of the species-specific peptide pheromone cCF10 and modification of the active region of the antimicrobial peptide. The results showed that cCF10-C4 possessed specific antimicrobial activity against E. faecalis and was not active against other types of bacteria tested. The specificity of this hybrid peptide was shown by the absence of antimicrobial effects in the pheromone-substituted derivative. Further studies indicated that cCF10-C4 and its parent peptide C4 exert their activities by damaging cytoplasmic membrane integrity. The present study reveals the application potential of these molecules as “probiotic” antimicrobials for the control of specific bacterial infections, and it also helps to elucidate the design and construction of species-specific antimicrobials with precise targeting specificity.
Highlights
Www.nature.com/scientificreports effective weapons against pathogenic microorganisms such as multidrug-resistant microbes and are amongst the most promising candidates for a new generation of antimicrobial agents
To ensure that the targeting domain and the killing domain remain functionally and structurally independent, a flexible peptide linker (GGG) was incorporated between the two functional domains. Biological testing of these peptides showed that the addition of cCF10 at the N terminus of C6 significantly increased antimicrobial activity against E. faecalis relative to C6 alone; the hybrid peptides still possessed antimicrobial activities against the other bacteria tested. We reasoned that these undesired bactericidal effects against unrelated bacteria might arise from a high density of positive charges, which contributes to AMPs attraction toward and attachment to anionic bacteria cell membranes
Our results indicated that the cCF10-C4 peptide results in a significant increase in the degree of cytoplasmic membrane depolarization in E. faecalis compared to C4 alone (Fig. 2), which correlates with their antibacterial activities against the targeted bacteria
Summary
Www.nature.com/scientificreports effective weapons against pathogenic microorganisms such as multidrug-resistant microbes and are amongst the most promising candidates for a new generation of antimicrobial agents. Several attempts have been made to construct pathogen-selective antimicrobials by conjugating a bacterial recognition domain to antimicrobial peptides or bactericidal proteins[20,21,22,23,24,25] These findings provided an intriguing starting point for the development of multidomain AMPs with selective bactericidal effects against specific bacteria. The main reason for this problem may lay in the fact that the killing moiety of these fusion peptides had not been redesigned or modified, and electrostatic attractions between cationic peptide molecules and anionic lipids of the bacterial membrane were retained, thereby causing indiscriminant bactericidal effect via a non-receptor-mediated pathway These approaches have yet to generate target-specific antimicrobials. The aim of the present study is to provide a rational approach to convert normally wide-spectrum antimicrobial peptides into “smart” targeted antimicrobials with precise specificity against target organisms without damaging benign bystanders
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.