Koehbach, J; Gani, J; Hilpert, K; Craik, DJ
(2021)
Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens.
Microorganisms, 9 (6).
p. 1249.
ISSN 2076-2607
https://doi.org/10.3390/microorganisms9061249
SGUL Authors: Hilpert, Kai
Abstract
According to the World Health Organization (WHO) the development of resistance against antibiotics by microbes is one of the most pressing health concerns. The situation will intensify since only a few pharmacological companies are currently developing novel antimicrobial compounds. Discovery and development of novel antimicrobial compounds with new modes of action are urgently needed. Antimicrobial peptides (AMPs) are known to be able to kill multidrug-resistant bacteria and, therefore, of interest to be developed into antimicrobial drugs. Proteolytic stability and toxicities of these peptides are challenges to overcome, and one strategy frequently used to address stability is cyclization. Here we introduced a disulfide-bond to cyclize a potent and nontoxic 9mer peptide and, in addition, as a proof-of-concept study, grafted this peptide into loop 6 of the cyclotide MCoTI-II. This is the first time an antimicrobial peptide has been successfully grafted onto the cyclotide scaffold. The disulfide-cyclized and grafted cyclotide showed moderate activity in broth and strong activity in 1/5 broth against clinically relevant resistant pathogens. The linear peptide showed superior activity in both conditions. The half-life time in 100% human serum was determined, for the linear peptide, to be 13 min, for the simple disulfide-cyclized peptide, 9 min, and, for the grafted cyclotide 7 h 15 min. The addition of 10% human serum led to a loss of antimicrobial activity for the different organisms, ranging from 1 to >8-fold for the cyclotide. For the disulfide-cyclized version and the linear version, activity also dropped to different degrees, 2 to 18-fold, and 1 to 30-fold respectively. Despite the massive difference in stability, the linear peptide still showed superior antimicrobial activity. The cyclotide and the disulfide-cyclized version demonstrated a slower bactericidal effect than the linear version. All three peptides were stable at high and low pH, and had very low hemolytic and cytotoxic activity.
Item Type: |
Article
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Additional Information: |
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: |
ESKAPE, MCoTI-II, antimicrobial peptide, cyclotide, cysteine cyclization, serum activity, stability, antimicrobial peptide, cyclotide, cysteine cyclization, ESKAPE, serum activity, stability, MCoTI-II |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
Microorganisms |
ISSN: |
2076-2607 |
Language: |
eng |
Dates: |
Date | Event |
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8 June 2021 | Published | 4 June 2021 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
Project ID | Funder | Funder ID |
---|
FL150100146 | Australian Research Council | http://dx.doi.org/10.13039/501100000923 | CE200100012 | Centre of Excellence for Innovations in Peptide and Protein Science | UNSPECIFIED | KH001 | St George's, University of London, Institute of Infection and Immunity start-up grant | UNSPECIFIED |
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PubMed ID: |
34201398 |
Web of Science ID: |
WOS:000666084300001 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113410 |
Publisher's version: |
https://doi.org/10.3390/microorganisms9061249 |
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