Abstract
Antimicrobial peptides (AMPs) are found in nearly all living organisms, show broad spectrum antibacterial activity, and can modulate the immune system. Furthermore, they have a very low level of resistance induction in bacteria, which makes them an ideal target for drug development and for targeting multi-drug resistant bacteria ‘Superbugs’. Despite this promise, AMP therapeutic use is hampered as typically they are toxic to mammalian cells, less active under physiological conditions and are susceptible to proteolytic degradation. Research has focused on addressing these limitations by modifying natural AMP sequences by including e.g., d-amino acids and N-terminal and amino acid side chain modifications to alter structure, hydrophobicity, amphipathicity, and charge of the AMP to improve antimicrobial activity and specificity and at the same time reduce mammalian cell toxicity. Recently, multimerisation (dimers, oligomer conjugates, dendrimers, polymers and self-assembly) of natural and modified AMPs has further been used to address these limitations and has created compounds that have improved activity and biocompatibility compared to their linear counterparts. This review investigates how modifying and multimerising AMPs impacts their activity against bacteria in planktonic and biofilm states of growth.
Highlights
As drug resistant bacterial infections increase globally, the age of antibiotics is reported to be coming to an end (O’Neill, 2016)
A promising avenue of research stems from naturally occurring antimicrobial peptides (AMPs) that have a broad spectrum of activity (Zasloff, 2002)
This study showed that independent of charge, longer peptides were generally more active than their shorter counterparts and that a minimal length of ∼17–19 residues was required for membrane disruption of E. coli, P. aeruginosa and S. aureus
Summary
As drug resistant bacterial infections increase globally, the age of antibiotics is reported to be coming to an end (O’Neill, 2016). They all caused less membrane damage to S. aureus compared to AR-23 These substitutions affected the overall hydrophobicity, helicity, and charge on these AMPs, making it difficult to determine the exact effect changes to amphipathicity have on antibacterial activity and toxicity. This indicated that individual residues and not just disruption of amphipathicity affects activity against different bacteria in different ways This again suggests that the different side groups of amino acids may play specific and important roles in AMP activity and interaction with bacterial membranes. At 40 μM they both showed 0% haemolysis In another set of synthesised peptides where 4 alanines were substituted with 4 leucines to increase overall hydrophobicity, 6K-F17-4L and 1KAMP-4L were created and the charge clustered 6K-F17-4L exhibited lower antimicrobial activity but was less haemolytic (33% haemolysis at 40 μM) than the more amphipathic analogues. A better understanding of the specific interactions between AMPs and bacterial membranes may assist in designing AMPs with increased antimicrobial activity but may allow for better cell specificity
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