Abstract

EeCentrocin 1 is a potent antimicrobial peptide isolated from the marine sea urchin Echinus esculentus. The peptide has a hetero-dimeric structure with the antimicrobial activity confined in its largest monomer, the heavy chain (HC), encompassing 30 amino acid residues. The aim of the present study was to develop a shorter drug lead peptide using the heavy chain of EeCentrocin 1 as a starting scaffold and to perform a structure-activity relationship study with sequence modifications to optimize antimicrobial activity. The experiments consisted of 1) truncation of the heavy chain, 2) replacement of amino acids unfavourable for in vitro antimicrobial activity, and 3) an alanine scan experiment on the truncated and modified heavy chain sequence to identify essential residues for antimicrobial activity. The heavy chain of EeCentrocin 1 was truncated to less than half its initial size, retaining most of its original antimicrobial activity. The truncated and optimized lead peptide (P6) consisted of the 12 N-terminal amino acid residues from the original EeCentrocin 1 HC sequence and was modified by two amino acid replacements and a C-terminal amidation. Results from the alanine scan indicated that the generated lead peptide (P6) contained the optimal sequence for antibacterial activity, in which none of the alanine scan peptides could surpass its antimicrobial activity. The lead peptide (P6) was also superior in antifungal activity compared to the other peptides prepared and showed minimal inhibitory concentrations (MICs) in the low micromolar range. In addition, the lead peptide (P6) displayed minor haemolytic and no cytotoxic activity, making it a promising lead for further antimicrobial drug development.

Highlights

  • Bacterial resistance to commercial antibiotics has increased severely over the last years

  • The N‐terminal has an abundance of hydrophobic and cationic residues, which is a characteristic known to be of importance for the activity of Antimicrobial peptides (AMPs).[19]

  • An eight‐fold decrease in potency was observed against the Gram‐negative test bacteria, maybe due to reduced charge of P2 compared to the full heavy chain (HC) peptide (Table 1)

Read more

Summary

Introduction

Bacterial resistance to commercial antibiotics has increased severely over the last years. AMPs efficiently kill bacterial pathogens with low toxicity to mammalian cells, and often have broad‐spectrum antimicrobial activity against pathogenic Gram‐ positive and Gram‐negative bacteria.[2,3,4] Most AMPs appear to interact with bacterial membranes, forming pores or aggregates at the membrane surface, causing cooperative permeabilization and loss of membrane integrity.[3] In membrane‐like environments, AMPs tend to form amphipathic structures, i.e. structures with separate hydrophobic and hydrophilic domains Their net positive charge facilitates interactions with the negatively charged bacterial membranes and/or cell walls, whereas their amphipathic character enables membrane permeabilization.[4] Because AMPs in general act on the lipid bilayer structure of bacterial membranes, there seems to be lower propensity of generating resistance against AMPs compared to other antibiotic classes.[5,6,7] There is even recent evidence that antibiotic‐resistant Escherichia coli display increased sensitivity towards AMPs.[8] Some AMPs have additional mode of actions, attacking both extracellular and intracellular targets rapidly.[8,9] Several AMPs are currently in the medical pipeline due to these favourable properties.[10,11,12,13]

Objectives
Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

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.