Abstract
The electrostatic interaction of the charge cluster of an amphipathic peptide antibiotic with microbial membranes is a salt-sensitive step that often determines organism specificity. We have examined the correlation between charge clusters and salt insensitivity and microbial specificity in linear, cyclic, and retro-isomeric cystine-stabilized beta-strand (CSbeta) tachyplesin (TP) in a panel of 10 test organisms. Cyclic tachyplesins consisting of 14 and 18 amino acids are constrained by an end-to-end peptide backbone and two or three disulfide bonds to cross-brace the anti-parallel beta-strand that approximates a "beta-tile" structure. Circular dichroism measurements of beta-tile TPs showed that they displayed ordered structures. Control peptides containing the same number of basic amino acids as TP but lacking disulfide constraints were highly salt sensitive. Cyclic TP analogues with six cationic charges were more broadly active and salt-insensitive than those with fewer cationic charges. Reducing their proximity or number of cationic charges, particularly those with three or fewer basic amino acids, led to a significant decrease in potency and salt insensitivity, but an increased selectivity to certain Gram-positive bacteria. An end-group effect of the dibasic N-terminal Lys of TP in the open-chain TP and its retroisomer was observed in certain Gram-negative bacteria under high-salt conditions, an effect that was not found in the cyclic analogs. These results suggest that a stable folded structure together with three or more basic amino acids closely packed in a charged region in CSbeta peptides is important for salt insensitivity and organism specificity.
Highlights
A common feature shared among the 500 antimicrobial peptides found in nature is their tendency to form amphipathic structures that cluster basic and hydrophobic amino acids into distinctive regions [1]
We have examined the correlation between charge clusters and salt insensitivity and microbial specificity in linear, cyclic, and retro-isomeric cystine-stabilized -strand (CS) tachyplesin (TP) in a panel of 10 test organisms
These results suggest that a stable folded structure together with three or more basic amino acids closely packed in a charged region in CS peptides is important for salt insensitivity and organism specificity
Summary
A common feature shared among the 500 antimicrobial peptides found in nature is their tendency to form amphipathic structures that cluster basic and hydrophobic amino acids into distinctive regions [1]. Cystine-stabilized -strand (CS) peptides belong to a major structural family of antimicrobial peptides that are characterized by one or more cystine bonds in their -strand scaffoldings This family is richly represented by defensins, protegrins, and tachyplesins that generally possess a cluster of three or more basic amino acids in their charged regions. Tachyplesins isolated from horseshoe crabs consisting of 17–19 amino acids contain two cross-bracing disulfides stabilizing an antiparallel -strand connected by a reverse turn as determined by two-dimensional NMR [10] They are similar in structure and activity profile to protegrins [11], a family of peptides found in pig intestines. This paper is available on line at http://www.jbc.org relatively small sizes, these peptides are attractive targets for structure-activity studies that may lead to therapeutics to treat infections
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