Structural Requirements for Potent Versus Selective Cytotoxicity for Antimicrobial Dermaseptin S4 Derivatives

Kustanovich, I. M.; Shalev, Deborah E.; Mikhlin, Masha; Gaidukov, Leonid; Mor, Amram

doi:10.1074/jbc.m111071200

Cited by 153 publications

(187 citation statements)

References 68 publications

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“…Regardless of structural class (i.e., ␣-helix, ␤-sheet, loop, or extended), nonselective AMPs typically (i) are very hydrophobic, such that their interactions with membranes are governed primarily by the hydrophobic effect (10)(11)(12)(13)(14)(15), and (ii) have a well defined amphipathic structure (4,11,(14)(15)(16)(17). In contrast, the antibacterial activity of selective AMPs depends on (i) high net cationic charge (12)(13)(14)18) (although excessive cationic charge can also lead to hemolytic activity) (18, 19) and (ii) only moderate hydrophobicity (16,19,21,22). Perhaps counterintuitively, a well defined amphipathic structure is not necessary for selective antimicrobial activity (7,16); destabilization of AMP secondary structure often leads to improvements in selectivity (15,20).…”

Section: Discussionmentioning

confidence: 99%

“…The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet (4), barrel-stave pore (4), toroidal pore (8), and aggregate (9) models. Nevertheless, a considerable number of structure-activity investigations have elucidated how the physicochemical properties of these molecules relate to their biological activities (4,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

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confidence: 99%

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Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Chongsiriwatana¹,

Patch²,

Czyzewski³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

575

578

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Antimicrobial peptides (AMPs) and their mimics are emerging as promising antibiotic agents. We present a library of ''ampetoids'' (antimicrobial peptoid oligomers) with helical structures and biomimetic sequences, several members of which have low-micromolar antimicrobial activities, similar to cationic AMPs like pexiganan. Broad-spectrum activity against six clinically relevant BSL2 pathogens is also shown. This comprehensive structure-activity relationship study, including circular dichroism spectroscopy, minimum inhibitory concentration assays, hemolysis and mammalian cell toxicity studies, and specular x-ray reflectivity measurements shows that the in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy. The ampetoids' antibacterial activity, coupled with their low cytotoxicity against mammalian cells, make them a promising class of antimicrobials for biomedical applications. Peptoids are biostable, with a protease-resistant N-substituted glycine backbone, and their sequences are highly tunable, because an extensive diversity of side chains can be incorporated via facile solid-phase synthesis. Our findings add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics.antibiotics ͉ peptidomimetics ͉ structure-activity studies N atural antimicrobial peptides (AMPs) defend a wide array of organisms against bacterial pathogens and show potential as supplements for or replacements of conventional antibiotics, because few bacteria have evolved resistance to them (1-3). Many AMPs kill bacteria by permeabilization of the cytoplasmic membrane, causing depolarization, leakage, and death (4), whereas others target additional anionic bacterial constituents (e.g., DNA, RNA, or cell wall components) (2, 5). Amphipathic secondary structures in which residues are segregated into hydrophobic and cationic regions ( Fig. 1 A and B) are the hallmark of most AMPs (6). Regardless of their final target of killing, AMPs must interact with the bacterial cytoplasmic membrane, and their amphipathicity is integral to such interactions (1, 2, 7). Additionally, their cationic nature imparts AMPs with some measure of selectivity, because mammalian cell membranes are largely zwitterionic. The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet (4), barrel-stave pore (4), toroidal pore (8), and aggregate (9) models. Nevertheless, a considerable number of structure-activity investigations have elucidated how the physicochemical properties of these molecules relate to their biological activities (4,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).Although AMPs have been actively studied for decades (23-25), they have yet to see widespread clinical use (1). This is due in part to the vulnerability of many peptide therapeutics to rapid in vivo degradation, which dramatically reduces their bioavailability. Nonnatural mimics of AMPs...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Chongsiriwatana¹,

Patch²,

Czyzewski³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

575

578

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“…Studies have demonstrated that high levels of hydrophobicity can decrease selectivity between the desired bacterial targets and host cells (136,275). Similarly, incorporation of charged residues above a certain maximum (varying with each peptide) does not lead to an increase in activity (46).…”

Section: Structural Requirements For Antibacterial Peptidesmentioning

confidence: 99%

Peptide Antimicrobial Agents

2006

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SUMMARY Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents.

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“…Due to its distinctive primary structure, dermaseptin S4 was used to identify structure-function relationships, which eventually led to potent derivatives (19,21,31,37,38). In recent work, we defined the activity of a single-amino-acid-substituted derivative, K 4 -S4, against Escherichia coli O157:H7 in terms of milieu dependencies (51).…”

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Antibacterial Properties of Dermaseptin S4 Derivatives under Extreme Incubation Conditions

Rydlo

Rotem

Mor

2006

Antimicrob Agents Chemother

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Antibacterial properties of the frog-derived peptide dermaseptin S4 and a series of synthetic derivatives against the food pathogen Escherichia coli O157:H7 were investigated under extreme incubation conditions. The 28-mer analog K 4 K 20 S4 (P 28 ) displayed an MIC of 8 M and rapid bactericidal kinetics under standard culture conditions. Potent bactericidal properties were maintained at high salt concentrations, under acidic or basic conditions, and at extreme temperatures. The N-terminal 14-mer sequence (P 14 ) displayed higher potency (MIC, 4 M) but only within a narrow range of incubation conditions, pointing to the importance of the C-terminal domain of P 28 . The potency range was reextended upon conjugation of aminododecanoic acid to P 14 . The resulting lipopeptide was even more potent (MIC, 2 M) and affected bacterial viability under most of the conditions tested, including in commercial apple juice. The mechanistic implications of peptides' hydrophobicity, charge, structure, and binding to an idealized membrane were probed and are discussed here. Collectively, the data indicate interest in simple peptide-based compounds for design of antimicrobials that affect pathogens under a variable range of incubation conditions. Antimicrobial peptides (AMPs) are important components of innate immunity (23, 39, 52). Many are active towards a wide range of microorganisms by a mode of action which is still not fully understood but is assumed to involve interaction with the bacterial membrane and its disruption. AMPs do not require interaction with a chiral center for activity, supporting a lower probability for microorganisms to develop efficient resistance mechanisms compared with conventional antibiotics (22,38).AMPs from the dermaseptin family were recently proposed as model peptides for investigating the effects of acyl conjugation (13,17,44). These amphibian-derived AMPs (35, 36) have been amply investigated during the past decade and shown to exert rapid cytolytic activity against a wide range of microorganisms, including gram-negative and gram-positive bacteria, protozoa, filamentous fungi (14,26,35,36), spores of pathogenic bacteria (29), yeasts (11), and intracellular parasites (13,17,30), as well as antiviral activity (5).Due to its distinctive primary structure, dermaseptin S4 was used to identify structure-function relationships, which eventually led to potent derivatives (19,21,31,37,38). In recent work, we defined the activity of a single-amino-acid-substituted derivative, K 4 -S4, against Escherichia coli O157:H7 in terms of milieu dependencies (51). Extending that study, the present work is aimed at understanding the molecular elements in native dermaseptin S4 that are necessary for maintaining antimicrobial potency under extreme incubation conditions. We produced a set of derivatives that varied in length, composition, hydrophobicity, and net charge and investigated the effect of incubation conditions on the peptides' activity and bacterial susceptibility. In addition, we investigated the peptides' ...

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Structural Requirements for Potent Versus Selective Cytotoxicity for Antimicrobial Dermaseptin S4 Derivatives

Cited by 153 publications

References 68 publications

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Peptide Antimicrobial Agents

Antibacterial Properties of Dermaseptin S4 Derivatives under Extreme Incubation Conditions

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