Abstract
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide–lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising d-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.
Highlights
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections
Identified in the Winter Flounder[5], Pleuronectes americanus, pleurocidin is a potent AMP with broad spectrum antibacterial activity that acts by damaging the plasma membrane[6], with activity that is dependent on their ability to adopt an amphipathic α-helix conformation[7]
It is well established, that many AMPs can disrupt bacterial cell metabolism, in addition to, or in place of, their well-known membrane damaging action[8]. Pleurocidin is one such AMP and previous work supports the view that its high potency, at least against Gram-negative bacteria, such as Escherichia coli, is linked to its ability to cross the bacterial plasma membrane and penetrate within bacteria to attack intracellular targets[9,10]
Summary
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. An analogue comprising Damino acids was well tolerated at an intravenous dose of 15 mg/kg and effective as vancomycin in reducing EMRSA-15 lung CFU This highlights the therapeutic potential of systemically delivered, bactericidal AMPs. Pharmacology, King’s College London, London, UK. Identified in the Winter Flounder[5], Pleuronectes americanus, pleurocidin is a potent AMP with broad spectrum antibacterial activity that acts by damaging the plasma membrane[6], with activity that is dependent on their ability to adopt an amphipathic α-helix conformation[7] It is well established, that many AMPs can disrupt bacterial cell metabolism, in addition to, or in place of, their well-known membrane damaging action[8]. We hypothesised that substituting arginine for each of the four lysine residues (Lys[7], Lys[8], Lys[14], Lys[18]; pleurocidin-KR Table 1) would directly increase hydrogen bonding between the peptide and the lipid headgroups, shifting the balance away from intramolecular hydrogen bonding that stabilises more ordered α-helix conformations
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