Potential Therapeutic Applications of Magainins and other Antimicrobial Agents of Animal Origin

Jacob, Leonard S.; Zasloff, Michael

doi:10.1002/9780470514658.ch12

Cited by 89 publications

(57 citation statements)

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“…This is true for many multicellular organisms including both vertebrate and invertebrate animals (1)(2)(3)(4). Many families of AMPs have been identified, and some are of particular interest for direct application to human health (5)(6)(7). In addition to direct therapeutic application of native AMPs, the potential exists for the enhancement of activity through the use of synthetic peptide derivatives that incorporate atypical or nonnative amino acids, so as to resist natural metabolic proteases, enhance pathogen specificity, and increase effectiveness (8 -10).…”

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confidence: 99%

Solution Structure of Synthetic Penaeidin-4 with Structural and Functional Comparisons with Penaeidin-3

Cuthbertson

Yang

Bachère

et al. 2005

Journal of Biological Chemistry

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Antimicrobial peptide structure has direct implications for the complexity of functions and mechanisms of action. The penaeidin antimicrobial peptide family from shrimp is divided into multiple class designations based on primary structure. The penaeidin classes are not only characterized by variability in primary sequence but also by variation in target specificity and effectiveness. Whereas class 4 exhibits low isoform diversity within species and is highly conserved between species, the primary sequence of penaeidin class 3 is less conserved between species and exhibits considerable isoform diversity within species. All penaeidins, regardless of class or species, are composed of two dramatically different domains: an unconstrained proline-rich domain and a disulfide bond-stabilized cysteine-rich domain. The proline-rich domain varies in length and is generally less conserved, whereas the spacing and specific residue content of the cysteine-rich domain is more conserved. The structure of the synthetic penaeidin class 4 (PEN4-1) from Litopenaeus setiferus was analyzed using several approaches, including chemical mapping of disulfide bonds, circular dichroism analysis of secondary structural characteristics, and complete characterization of the solution structure of the peptide by proton NMR. L. setiferus PEN4-1 was then compared with the previously characterized structure of penaeidin class 3 from Litopenaeus vannamei. Moreover, the specificity of these antimicrobial peptides was examined through direct comparison of activity against a panel of microbes. The penaeidin classes differ in microbial target specificity, which correlates to variability in specific domain sequence. However, the tertiary structure of the cysteine-rich domain and indeed the overall structure of penaeidins are conserved across classes.Antimicrobial peptides (AMPs) 1 can form a physiochemical barrier that deters infection by potential pathogens in an individual organism. This is true for many multicellular organisms including both vertebrate and invertebrate animals (1-4). Many families of AMPs have been identified, and some are of particular interest for direct application to human health (5-7). In addition to direct therapeutic application of native AMPs, the potential exists for the enhancement of activity through the use of synthetic peptide derivatives that incorporate atypical or nonnative amino acids, so as to resist natural metabolic proteases, enhance pathogen specificity, and increase effectiveness (8 -10).Penaeidins are known to be a diverse family of cationic peptides that, despite their extensive variability in primary structure, target in an almost exclusive manner Gram(ϩ) bacteria and fungi (11, 12). Variability in primary structure has been noted in the form of multiple classes (designated 1/2, 3, and 4) and multiple isoforms of some classes (13).The typical penaeidin molecule is composed of two domains, an unconstrained proline-rich N-terminal domain (PRD) and a cysteine-rich domain (CRD) with a stable ␣-helical structure...

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Solution Structure of Synthetic Penaeidin-4 with Structural and Functional Comparisons with Penaeidin-3

Cuthbertson

Yang

Bachère

et al. 2005

Journal of Biological Chemistry

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“…This has led to many AMPs, such as pexiganan (analogue of magainin), gramicidins, polymyxin, nisin, daptomycin, and defensin-mimetic molecule, being entered into clinical trials (2)(3)(4)(5)(6). However, it has been argued in several in vitro studies and recent reports that the use of AMPs in therapeutic amounts over an extended period of time might lead to reduced susceptibility due to adaptive changes in phenotypic and genotypic characteristics of the organism (7)(8)(9)(10)(11)(12)(13).…”

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Differential Adaptive Responses of Staphylococcus aureus to In Vitro Selection with Different Antimicrobial Peptides

Shireen

Singh

Das

et al. 2013

Antimicrob Agents Chemother

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We subjected Staphylococcus aureus ATCC 29213 to serial passage in the presence of subinhibitory concentrations of magainin 2 and gramicidin D for several hundred generations. We obtained S. aureus strains with induced resistance to magainin 2 (strain 55MG) and gramicidin D (strain 55GR) that showed different phenotypic changes in membrane properties. Both exhibited a change in membrane phospholipid content and an increase in membrane rigidity, while an alteration in net charge compared to that of the control occurred only in the case of 55MG.T he growing problem of resistance to conventional antibiotics in pathogens like Staphylococcus aureus and the need for new alternatives has stimulated interest in the development of antimicrobial peptides (AMPs) as human therapeutics (1). This has led to many AMPs, such as pexiganan (analogue of magainin), gramicidins, polymyxin, nisin, daptomycin, and defensin-mimetic molecule, being entered into clinical trials (2-6). However, it has been argued in several in vitro studies and recent reports that the use of AMPs in therapeutic amounts over an extended period of time might lead to reduced susceptibility due to adaptive changes in phenotypic and genotypic characteristics of the organism (7-13). Therefore, the aim of our study was to examine whether S. aureus bacteria, on continuous exposure to sublethal concentrations of certain well-studied AMPs (magainin 2 and gramicidin D), alter their susceptibility and whether resistant strains are selected. Since the putative mechanism of action of the AMPs studied involves targeting of the bacterial membrane, analyses of various cell membrane (CM) parameters were performed to understand their role in the in vitro-selected strains. (This study was presented in part at the 113th General Meeting, American Society for Microbiology, Denver, CO, 18 to 21 May 2013.) To generate AMP-resistant strains, S. aureus ATCC 29213 was chosen and two cell lines were maintained for each peptide in Mueller-Hinton broth (MHB). Serial passage was done in two cell lines for each AMP, one in the presence of noninhibitory and increasing AMP concentrations (positive-selection line) and the other in the absence of peptide (control selection line), as described elsewhere (10). The experiment was conducted for 55 serial passages, constituting 600 to 700 bacterial generations. Each transfer was given a strain designation to indicate the serial passage number. After every 5 transfers, evolution of resistance in the positive-selection line against magainin 2 and gramicidin D was identified by determining the MIC in MHB, following NCCLS guidelines (14). Further confirmation of resistance was done by performing a bactericidal assay as described before (15,16).The development of resistance occurred for both of the AMPs studied, as indicated by a gradual rise in MIC values with increasing passage number in the positive-selection lines compared to the MICs in the respective control selection lines. At the 55th passage, the positive-selection strains showed an Ն8-and ...

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“…Cationic antimicrobial peptides (CAMPs) have been considered possible alternatives to traditional antibiotics due to their interaction with bacterial membranes (3)(4)(5)(6), which allows activity against metabolically dormant bacteria that are often found at the center of biofilms (7). Moreover, peptides that target the bacterial membrane are less likely to cause bacterial resistance since multifactorial resistance mechanisms are required at the cell membrane (5).…”

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Antimicrobial Peptide GL13K Is Effective in Reducing Biofilms of Pseudomonas aeruginosa

Hirt

Gorr

2013

Antimicrob Agents Chemother

105

102

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Human parotid secretory protein (PSP; BPIF2A) is predicted to be structurally similar to bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. Based on the locations of known antimicrobial peptides in the latter two proteins, potential active peptides in the PSP sequence were identified. One such peptide, GL13NH 2 (PSP residues 141 to 153) was shown previously to interfere with LPS binding and agglutinate bacteria without bactericidal activity. By introducing three additional positively charged lysine residues, the peptide was converted to the novel bactericidal cationic peptide GL13K (MIC for Pseudomonas aeruginosa, 8 g/ml [5.6 M]). We investigated the antibiofilm activity of GL13K against static, monospecies biofilms of P. aeruginosa PAO1. Two-hour exposure of a 24-h biofilm to 64 g/ml (44.8 M) GL13K reduced biofilm bacteria by 10 2 , and 100 g/ml (70 M) GL13K reduced bacteria by 10 3 . Similar results could be achieved on 48-h-old biofilms. Lower concentrations of GL13K (32 g/ml [22.4 M]) were successful in reducing biofilm cell numbers in combination with tobramycin. This combination treatment also achieved total eradication of the biofilm in a majority (67.5%) of tested samples. An alanine scan of GL13K revealed the importance of the leucine residue in position six of the peptide sequence, where replacement led to a loss of antibiofilm activity, whereas the impact of replacing charged residues was less pronounced. Bacterial metalloproteases were found to partially inactivate GL13K but not a D amino acid version of the peptide.

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Potential Therapeutic Applications of Magainins and other Antimicrobial Agents of Animal Origin

Cited by 89 publications

References 88 publications

Solution Structure of Synthetic Penaeidin-4 with Structural and Functional Comparisons with Penaeidin-3

Solution Structure of Synthetic Penaeidin-4 with Structural and Functional Comparisons with Penaeidin-3

Differential Adaptive Responses of Staphylococcus aureus to In Vitro Selection with Different Antimicrobial Peptides

Antimicrobial Peptide GL13K Is Effective in Reducing Biofilms of Pseudomonas aeruginosa

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