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  • Title: Antimicrobial action of prototypic amphipathic cationic decapeptides and their branched dimers.
    Author: Dewan PC, Anantharaman A, Chauhan VS, Sahal D.
    Journal: Biochemistry; 2009 Jun 23; 48(24):5642-57. PubMed ID: 19432402.
    Abstract:
    Toward delineation of antimicrobial action, a prototypic amphipathic, cationic decapeptide Ac-G-X-R-K-X-H-K-X-W-A-NH(2) was designed and peptides for which X was didehydrophenylalanine (DeltaFm), alpha-aminoisobutyric acid (Um), or phenylalanine (Fm) were synthesized. A growth kinetics experiment indicated that the bacteriostatic effects were nil (Um), mild and transient (Fm), and strong and persistent (DeltaFm) respectively. Though at par in binding to lipopolysaccharide, DeltaFm and Fm, but not Um, caused outer membrane permeabilization. Inner membrane permeabilization was attenuated and membrane architecture rehabilitated with DeltaFm but not Fm. Reverse phase high-performance liquid chromatography revealed that DeltaFm was translocated into Escherichia coli, while Um and fragments of Fm were detected in the medium. Among these monomers, only DeltaFm was modestly antibiotic [minimum inhibitory concentrations (MICs) of 110 microM (E. coli) and 450 microM (Staphylococcus aureus)]. Interestingly, a linear dimer of DeltaFm, viz. (DeltaFm)(2), turned out to be highly potent against E. coli [MIC of 2 microM and minimum bactericidal concentration (MBC) of 2 microM] and modestly potent against S. aureus (MIC of 20 microM and MBC of 20 microM). In contrast, a lysine-based branched dimer of DeltaFm, viz. DeltaFd, was found to be a potent antimicrobial against both E. coli (MIC of 2.5 microM) and S. aureus (MIC of 5 microM). Studies with analogous branched dimers of Fm and Um have indicated that dimerization represents a scaffold for potentiation of antimicrobial peptides and that the presence of DeltaF confers potent activity against both E. coli and S. aureus. De novo design has identified DeltaFd as a potent, noncytotoxic, bacterial cell-permeabilizing and -penetrating antimicrobial peptide, more protease resistant than its monomeric counterpart. We report that in comparison to the subdued and sequential "membrane followed by cell interior" mode of action of the monomeric DeltaFm, the strong and simultaneous "membrane along with cell interior" targeting by the dimeric DeltaFd potentiates and broadens its antibiotic action across the Gram-negative-Gram-positive divide.
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