Miruna Serian:Emergent conformational and aggregation properties of synergistic antimicrobial peptide combinations†

Despite this, the development of new antibiotics has declined, and the World Health Organisation (WHO) describes the antibacterial clinical and preclinical pipeline as stagnant and far from meeting global needs.1Therefore, there is an urgent need for increased efforts to develop alternatives to current antimicrobial agents. Consequently, the generation of novel medications to control and treat infections caused by multidrug-resistant pathogens has become a pressing priority for the scientific community. Antimicrobial peptides have quickly gained traction as promising drug candidates because of their potency against both Gram-negative and Gram-positive bacteria.2

Antimicrobial peptides are evolutionary conserved components of the immune system, found in almost all life forms, from prokaryotes to humans,3 and have been shown to have distinct roles. While in higher life forms they are produced to protect the host against infection, bacteria can also produce AMPs to kill other bacteria competing for the same environment.4 Despite their potential, several challenges hinder the widespread use of antimicrobial peptides as antibiotics alternatives. These include concerns about host toxicity,5 the emergence of bacterial resistance6 and high production costs.7

 To address these limitations, combining different antimicrobial peptides has emerged as a promising strategy. Similar to combination therapy with traditional drugs, combining antimicrobial peptides can lead to synergistic effects, potentially reducing the necessary dosage, minimising side effects, and lowering the risk of resistance development.8 Despite the benefits of synergistic combinations of AMPs, the mechanisms of their synergy are not yet fully understood. Computational and experimental studies have proposed several mechanisms, including pore formation. For instance, combining PGLa and MAG2, two peptides produced in the skin of Xenopus laevis can lead to the formation of a toroidal pore structure, that can in turn lead to more membrane disruption.9 In other cases, such as the interaction between the two AMPs produced by bumblebees, abaecin and the pore forming AMP hymenoptaecin, distinct mechanisms are observed; hymenoptaecin forms membrane pores, destabilising bacterial membranes and allowing abaecin entry into bacterial cells.10 Abaecin can also synergise with pore-forming peptides from other organisms.11

Additionally, †Electronic supplementary information (ESI) available: Workflow for the unsupervised machine learning methodology, conformational clusters data, residue level contact maps for different conformational clusters, peptide–lipid interactions, cluster centrality values. See DOI: https://doi.org/10.1039/d4nr03043e a Biological Physics & Soft Matter Group, Department of Physics, King’s College London, London, WC2R 2LS, UK b Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Science, King’s College London, London SE1 9NH, UK c Department of Engineering, King’s College London, London, WC2R 2LS, UK. E-mail: chris.lorenz@kcl.ac.uk This journal is © The Royal Society of Chemistry 2024 Nanoscale Open Access Article. Published on 15 October 2024. Downloaded on 10/21/2024 9:39:52 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online View Journal synergistic behaviour may arise from complementary mechanisms, such as in the case of coleoptericin and defensin. Coleoptericin acts to improve host survival while defensin can reduce bacterial load.12 

Overall, pore formation or peptide aggregation remains among the most suggested mechanisms of action for synergistic peptides. Further, there is a scarcity of research concerning the synergy between antimicrobial peptides originating from the same species. Previous work has investigated the synergy between the family of Winter Flounder (WF) peptides employing an interdisciplinary approach of microbiology, biophysics and electrophysiology.13 Despite only two out of the six WF peptides exhibiting potent antimicrobial activity when used individually, the study identified a series of two-way combinations that were active against both Gram-positive and Gramnegative bacteria. The Winter Flounder peptides are a family of peptides extracted from the Pseudopleuronectes americanus fish and they are found in the gills and intestines, as well as the skin of the fish.14–16 Among the six peptides, pleurocidin (or WF2) is the most studied peptide due to its broad spectrum antimicrobial activity.17–20 Pleurocidin functions through a combination of membrane destabilisation and metabolic inhibition. While all six WF peptides share some sequence similarity, the majority exhibit limited efficacy against bacteria, except for pleurocidin. The conformational flexibility of AMPs is considered to be crucial for their antibacterial potency.20–22

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