The cytoplasmic membrane of Staphylococcus aureus contains ϳ20 mol% of the net cationic lipid lysyl-phosphatidylglycerol (LPG). Elevated fractions of LPG are associated with increased resistance to cationic antibiotics, including the lipopeptide daptomycin (DAP). Although the surface charge of the bacterial cytoplasmic membrane is altered by LPG, surface binding of DAP was found to be only moderately affected in anionic vesicles containing 20 mol% LPG. These results suggest that charge repulsion cannot fully explain LPG-mediated resistance to cationic peptides. L ysylated phosphatidylglycerol (LPG) is a common aminoacylated phospholipid in the cytoplasmic membranes (CMs) of Staphylococcus aureus, where it constitutes about 20 mol% of the total CM phospholipid fraction (1-4). Phosphatidylglycerol (PG) is the most abundant phospholipid in S. aureus, imparting an overall negative surface charge to the bacterial CM. In LPG, lysine is esterified to the glycerol headgroup of PG, effectively replacing an anionic lipid with one that carries a net cationic charge. Elevated levels of LPG correlate with resistance to killing by the cationic, calcium-dependent lipopeptide daptomycin (DAP), as well as cationic host defense peptides in S. aureus and Listeria spp.(5-12). The effect of LPG on the efficacy of cationic antimicrobial peptides has been attributed to the reduced negative surface charge of the cytoplasmic membrane as a consequence of the aminoacylation of PG to LPG (13). This interpretation was challenged in a liposomal model system in which LPG levels typically found in clinical S. aureus strains only minimally affected binding of the alpha-helical antimicrobial peptides RP-1, cecropin A, and mastoparan X (14, 15). In those cases, the protective effect of lysylated phospholipids against antimicrobial peptides was attributed to a stabilization of the bilayer in the presence of lysylated phospholipids, leading to significantly reduced peptide-induced CM perturbations.RP-1, cecropin A, and mastoparan X belong to a class of short, linear cationic peptides that adopt an alpha-helical conformation when bound to lipid membranes. DAP, like RP-1, cecropin A, and mastoparan X, binds with preference to the anionic CMs typically found in prokaryotes; yet, it differs from this class of peptides in several important aspects. DAP is a tridecapeptide, in which the 10 C-terminal amino acids are cyclized. The N-terminal amino acid, tryptophan, is amidated with n-decanoic acid, which enhances binding to lipid bilayers (16). The amino acid composition is unusual in that two residues, 3-methyglutamate and the highly fluorescent species kynurenine, are nonproteinogenic. In contrast to linear, alpha-helical peptides, native DAP binds to lipid bilayers only in the presence of calcium, and its activity is absolutely calcium dependent (13,17).DAP is clinically important in the treatment of multidrug-resistant infections, including those caused by methicillin-resistant S. aureus (MRSA) strains. It is unclear if the binding of DAP to lipid bil...
Daptomycin is a cyclic lipopeptide of clinical importance in the treatment of multidrug resistant infections, including those caused by methicillinresistant S. aureus strains. Similar to many other antimicrobial peptides, daptomycin binds with preference to anionic membranes such as those typically found in prokaryotes. However, in contrast to most linear α-helical peptides, daptomycin binds to lipid bilayers only in the presence of calcium ions, and its activity in vivo is absolutely Ca 2+ -dependent. Here, we describe the early events that occur in the binding of daptomycin to lipid bilayers using a quantitative model to analyze both equilibrium and kinetic binding data. The goal of the analysis was to obtain a precise description of the early events that occur in the interaction of daptomycin with lipid and calcium ions at low daptomycin concentrations. In the course of the analysis, we also determined the rate and equilibrium constants for binding of daptomycin to lipid and Ca 2+ . The model used to describe the experimental data comprises a soluble daptomycin monomer that binds calcium ions in solution with low affinity, a soluble, Ca 2+ -bound dimer, and a 1:1 daptomycin−lipid Ca complex. A strong interaction of daptomycin with Ca 2+ -complexed lipid, the amount of which depends on the availability of calcium ions in the bulk solution, appears central to its function.
Antimicrobial peptides (AMPs) are an ancient, powerful, and ubiquitous component of the innate immune defence in all domains of life and play a key role in controlling the human microbiome. Many AMPs are known to
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