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    The pH-dependence of lipid-mediated antimicrobial peptide resistance in a model staphylococcal plasma membrane: A two-for-one mechanism of epithelial defence circumvention

    Year: 2019

    Journal: Eur. J. Pharm. Sci., Volume 128, 1-Feb, page 43–53

    Authors: Rehal, Reg; Gaffney, Piers R. J.; Hubbard, Alasdair T. M.; Barker, Robert D.; Harvey, Richard D.

    Organizations: Biotechnology and Biological Sciences Research Council (UK)Biotechnology and Biological Sciences Research Council (BBSRC); St. George's, University of London; Next Generation Facility Users Grant from the Engineering and Physical Sciences Research Council (UK) [EP/G068569/1]

    Country: Athens, GREECE

    Keywords: Lysylphosphatidylglycerol; Antimicrobial resistance; Antimicrobial peptides; Neutron reflectivity

    The mechanisms of membrane defence by lysylphosphatidylglycerol (LPG), were investigated using synthetic biomimetic mono-and bilayer models of methicillin resistant S. aureus ST239 TW, based on its lipid composition in both pH 7.4 (28% LPG) and pH 5.5 (51% LPG) cultures. These models incorporated a stable synthetic analogue of LPG (3adLPG) to facilitate long-duration biophysical studies, which were previously limited by the lability native LPG. Both increased 3adLPG content and full headgroup ionization at pH 5.5, increased bilayer order and dampened overall charge, via the formation of neutral ion pairs with anionic lipids. Ion pair formation in air/liquid interface lipid monolayers elicited a significant condensing effect, which correlated with the inhibition of subphase-injected magainin 2 F5W partitioning. In fluid phase lipid vesicles, increasing the proportion of 3adLPG from 28 to 51 mol% completely inhibited the adoption of the membrane-active alpha-helical conformation of the peptide, without the need for full headgroup ionization. Neutron reflectivity measurements performed on biomimetic PG/3adLPG fluid floating bilayers, showed a significant ordering effect of mild acidity on a bilayer containing 30 mol% 3adLPG, whilst peptide binding/partitioning was only fully inhibited in a bilayer with 55 mol% 3adLPG at pH 5.5. These findings are discussed with respect to the roles of LPG in resistance to human epithelial defences in S. aureus and the continued evolution of this opportunistic pathogen's virulence.
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