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Novel therapies based on cationic antimicrobial peptides 总被引:1,自引:0,他引:1
Pereira HA 《Current pharmaceutical biotechnology》2006,7(4):229-234
Cationic antimicrobial peptides serve as critical defense molecules protecting the host from invading bacteria, viruses and fungi. These antimicrobial peptides are widely distributed in nature and in vertebrates they have been localized to numerous tissues and cells. Cationic antimicrobial peptides can be expressed constitutively or under certain circumstances they can be induced in response to infection, inflammatory mediators, and cytokines. Although, their original and primary function was believed to be antimicrobial, it is now becoming clear that these antimicrobial peptides have a wide repertoire of functions with interesting ramifications on the immune system that are not solely antimicrobial. An area of active research is the determination of the mechanism(s) of action of antimicrobial peptides which have yet to be clarified. However, current consensus is that the mechanism is sufficiently different from conventional antibiotics that the development of resistance could be remote. Their broad spectrum activity, low potential to induce resistance and diverse functions make antimicrobial peptides an attractive family of compounds that have potential to be developed as therapeutics for treating certain infections. 相似文献
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The use of technetium-99m radiolabeled human antimicrobial peptides for infection specific imaging 总被引:1,自引:0,他引:1
Brouwer CP Sarda-Mantel L Meulemans A Le Guludec D Welling MM 《Mini reviews in medicinal chemistry》2008,8(10):1039-1052
Bacterial resistance to conventional antibiotics poses a challenge medicine to search for alternatives. Cationic antimicrobial peptides (AMPs) are promising for the development of a new class of antibiotics. This review focuses on the use of technetium-99m labeled synthetic AMPs, derived from human natural cationic AMPs, for target-delivery to and in vivo detection of infection sites caused by (drug-resistant) micro-organisms. The scintigraphic approach has proven to be a reliable method for evaluating AMPs in pharmacological studies and for optimizing target-delivery of radiolabeled AMPs to pathological sites in animals and humans. In addition, the effect of alterations in amphipathicity, amino acid substitution, and dimerization on the biological performance of AMPs is reported. Radiolabeled AMPs offer good perspectives for diagnosis of infections, for monitoring therapy, and, most importantly, for the ability to discriminate between infections and sterile inflammatory processes. 相似文献
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Over the past decade, levels of bacterial resistance to antibiotics have risen dramatically and "superbugs" resistant to most or all available agents have appeared in the clinic. Thus there is a growing need to discover and introduce new drugs. One potential source of novel antibiotics is the cationic antimicrobial peptides, which have been isolated from most living entities as components of their non-specific defenses against infectious organisms. Based on these natural templates, scores of structurally diverse antimicrobial cationic peptides have been designed, manufactured both chemically and biologically, and tested for activity against specific pathogens. A few of these peptide antibiotics have entered clinical trials to date, with mixed success. However, their diverse portfolio of structures, activity spectra, biological activities, and modes of action, provide substantial potential. 相似文献
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M. Jelokhani‐Niaraki E.J. Prenner C.M. Kay R.N. McElhaney R.S. Hodges 《Chemical biology & drug design》2002,60(1):23-36
Abstract: To investigate the role of peptide–membrane interactions in the biological activity of cyclic cationic peptides, the conformations and interactions of four membrane‐active antimicrobial peptides [based on Gramicidin S (GS)] were examined in neutral and negatively charged micelles and phospholipid vesicles, using CD and fluorescence spectroscopy and ultracentrifugation techniques. Moreover, the effects of these peptides on the release of entrapped fluorescent dye from unilamellar vesicles of phosphatidylcholine (PC) and phosphatidylethanolamine/phosphatidylglycerol (PE/PG) were studied. The cyclic peptides include GS10 [Cyclo(VKLdY P)2], GS12 [Cyclo(VKLKdY PKVKLdY P)], GS14 [Cyclo(VKLKVdY PLKVKLdY P)] and [d ‐Lys]4GS14 [Cyclo(VKLdK VdY PLKVKLdY P)] (underlined residues are d ‐amino acids), were different in their ring size, structure and amphipathicity, and covered a broad spectrum of hemolytic and antimicrobial activities. Interaction of the peptides with the zwitterionic PC and negatively charged PE/PG vesicles were distinct from each other. The hydrophobic interaction seems to be the dominant factor in the hemolytic activity of the peptides, as well as their interaction with the PC vesicles. A combination of electrostatic and hydrophobic interactions of the peptides induces aggregation and fusion in PE/PG vesicles with different propensities in the order: [d ‐Lys]4GS14 > GS14 > GS12 > GS10. GS10 and GS14 are apparently located in the deeper levels of the membrane interfaces and closer to the hydrophobic core of the bilayers, whereas GS12 and [d ‐Lys]4GS14 reside closer to the outer boundary of the interface. Because of differing modes of interaction of the cyclic cationic peptides with lipid bilayers, the mechanism of their biological activity (and its relation to peptide–lipid interaction) proved to be versatile and complex, and dependent on the biophysical properties of both the peptides and membranes. 相似文献
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Hancock RE 《Expert opinion on investigational drugs》1998,7(2):167-174
Novel classes of antibiotics that are useful against resistant bacteria are a major need in human medicine. Cationic antimicrobial peptides are utilised as nature's antibiotics, being produced constitutively or in response to infection in virtually every type of organism from plants and insects to man. Thus, these peptides are now being considered as potential antibiotics for infections. They have the following assets: structural diversity, rapid bactericidal action, a broad spectrum of activity that includes most of the clinically important resistant pathogens, and several ancillary activities which can include antifungal, antiviral, anti-endotoxin activities, and promotion of wound healing. Cationic peptides and proteins are now proceeding through clinical trials as topical antibiotics and anti-endotoxins. 相似文献
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《Expert opinion on investigational drugs》2013,22(2):167-174
Novel classes of antibiotics that are useful against resistant bacteria are a major need in human medicine. Cationic antimicrobial peptides are utilised as nature’s antibiotics, being produced constitutively or in response to infection in virtually every type of organism from plants and insects to man. Thus, these peptides are now being considered as potential antibiotics for infections. They have the following assets: structural diversity, rapid bactericidal action, a broad spectrum of activity that includes most of the clinically important resistant pathogens, and several ancillary activities which can include antifungal, antiviral, anti-endotoxin activities, and promotion of wound healing. Cationic peptides and proteins are now proceeding through clinical trials as topical antibiotics and anti-endotoxins. 相似文献
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Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus 总被引:8,自引:0,他引:8
The in vitro antiviral activity of antimicrobial cationic peptides: cecropin A, melittin, magainin I and II and indolicidin against the arenavirus Junin virus (JV), and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) was evaluated. Cecropin A effectively inhibited JV multiplication and failed to affect HSV replication whereas melittin impeded the multiplication of JV and HSV, but was highly toxic for the host cell. Magainins I and II exhibited inhibitory action toward HSV-1 and HSV-2 but were inactive against JV. Only indolicidin showed a direct inactivation effect on cell-free virus stocks. Besides its inhibitory effect on JV replication cecropin A also was active against the arenaviruses Tacaribe and Pichinde, mainly affecting late events of arenavirus multiplication cycle by preventing viral morphogenesis and egress from infected cells. 相似文献
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Strøm MB Haug BE Skar ML Stensen W Stiberg T Svendsen JS 《Journal of medicinal chemistry》2003,46(9):1567-1570
Cationic antibacterial peptides have been proclaimed as new drugs against multiresistant bacteria. Their limited success so far is partially due to the size of the peptides, which gives rise to unresolved issues regarding administration, bioavailability, metabolic stability, and immunogenicity. We have systematically investigated the minimum antibacterial motif of cationic antibacterial peptides regarding charge and lipophilicity/bulk and found that the pharmacophore was surprisingly small, opening the opportunity for development of short antibacterial peptides for systemic use. 相似文献
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Design and synthesis of cationic antimicrobial peptides with improved activity and selectivity against Vibrio spp 总被引:1,自引:0,他引:1
Chou HT Kuo TY Chiang JC Pei MJ Yang WT Yu HC Lin SB Chen WJ 《International journal of antimicrobial agents》2008,32(2):130-138
Extensive use of classical antibiotics has led to the growing emergence of many resistant strains of pathogenic bacteria. Evidence has suggested that cationic antimicrobial peptides (AMPs) are of greatest potential to represent a new class of antibiotics. The largest group of AMPs comprises peptides that fold into an amphipathic alpha-helical conformation when interacting with the target microorganism. In the current study, a series of cationic AMPs of 20 amino acids was designed and synthesised based on four structural parameters, including charge, polar angle, hydrophobicity and hydrophobic moment. The effect of these parameters on antimicrobial activity and selectivity was assessed by structural and biological analyses. Our results indicated that high hydrophobicity and amphipathicity (hydrophobic moment) were correlated with increased haemolytic activity, whilst antimicrobial activity was found to be less dependent on these factors. Three of the synthetic AMPs (GW-Q4, GW-Q6 and GW-H1) showed higher antimicrobial activity and selectivity against a broad spectrum of Gram-positive and Gram-negative bacteria compared with the naturally occurring AMPs magainin 2a and pleurocidin. This study also demonstrates that these rationally designed cationic and amphipathic helical AMPs exhibited high selectivity against several Vibrio spp. and are potential agents for future use in the treatment of these marine pathogens. 相似文献
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Antibacterial and lipopolysaccharide (LPS)-neutralising activity of human cationic antimicrobial peptides against periodontopathogens 总被引:1,自引:0,他引:1
Sung-Hoon Lee Hye-Kyoung Jun Hae-Ri Lee Chong-Pyoung Chung Bong-Kyu Choi 《International journal of antimicrobial agents》2010,35(2):138-145
In this study, we investigated the antibacterial activity of eight antimicrobial peptides (AMPs), comprising four human β-defensins (HBDs), three human neutrophil defensins (HNPs) and the cathelicidin LL-37, against two representative periodontopathogens, Prevotella intermedia and Tannerella forsythia. The neutralising effect of these AMPs on expression of interleukin (IL)-1β, IL-8 and intercellular adhesion molecule 1 (ICAM-1) induced by lipopolysaccharide (LPS) from P. intermedia and T. forsythia was also tested in THP-1 cells and human gingival fibroblasts. Prevotella intermedia was susceptible to HBD-3 and LL-37 but was resistant to HBD-1, HBD-2, HBD-4, HNP-1, HNP-2 and HNP-3 at concentrations up to 10 μM. However, all of the AMPs except HNP-2 at 5 μM significantly inhibited the expression of IL-1β, IL-8 and ICAM-1 induced by P. intermedia LPS. Tannerella forsythia showed marked susceptibility to the AMPs tested in the following order: LL-37, HBD-3, HBD-2, HBD-1, HNP-1 and HBD-4. All of the AMPs except HNP-3 had significant neutralising effects on T. forsythia LPS activity. The AMPs showing LPS-neutralising activity inhibited LPS binding to the cells. These results suggest that AMPs may be considered as preventive and therapeutic agents against mixed bacterial infections such as periodontitis by eliminating the pathogens themselves as well as reducing the activity of LPS. 相似文献
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Species across the evolutionary scale from insects to mammals deploy peptides to counter microbial invaders. Although, there are considerable differences in the primary and secondary structures of these peptides, they exert their antimicrobial activity by common mechanisms ie. by membrane permeabilization. Extensive structure-function studies have been carried out on this class of antimicrobial peptides and 'designer' peptides have been generated which possess specific antimicrobial activity. In this article the physico-chemical properties and biological activities of host-defense peptides and 'designer' peptides would be reviewed with a view to explore whether they could be used as effective therapeutic agents. 相似文献
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Using a surface plasmon resonance (SPR) system, we investigated the lipid membrane-binding properties of four analogues of the 18-residue linear amphipathic beta-sheet cationic antimicrobial peptide (KIGAKI)3-NH2, each of which contains a single isoleucine-to-tryptophan substitution. The results of the SPR study revealed significant differences in the binding characteristics of the peptides depending upon the position of tryptophan residues. These peptides showed higher binding affinity to membranes containing acidic phospholipids than zwitterionic phospholipids. The addition of dimethylsulfoxide to the running buffer was effective in maintaining the solubility of these peptide solutions and obtaining concentration-dependent sensorgrams for the kinetic analysis in this study. The kinetic binding data of SPR correlated closely with both the ability of the peptides to lyse liposomes with the same phospholipid composition and bactericidal activity. The results demonstrate that SPR may be a valuable tool to predict the membrane lytic properties of antimicrobial peptides. 相似文献
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Bruce C. Koppen Patrick P.G. Mulder Leonie de Boer Martijn Riool Jan W. Drijfhout Sebastian A.J. Zaat 《International journal of antimicrobial agents》2019,53(2):143-151
Antibiotic resistance and biofilm formation are the main reasons for failure in treatment of bacterial infections. This study aimed to identify synergistic combinations of conventional antibiotics and novel synthetic antimicrobial and antibiofilm peptides (SAAPs) inspired by the structures of the natural human cationic peptides LL-37 and thrombocidin-1 (TC-1). The LL-37-inspired lead peptide SAAP-148 was combined with antibiotics of different classes against Staphylococcus aureus, and showed synergy with teicoplanin. Synergy with teicoplanin was also observed with LL-37, the LL-37-inspired SAAP-276 and the TC-1-inspired TC84. Interestingly, no synergy was observed against Staphylococcus epidermidis. Furthermore, teicoplanin combined with SAAP-148 or SAAP-276 showed strong interaction against S. aureus biofilms. The dltABCD operon and the mprF gene in S. aureus conferred resistance to LL-37, but SAAP-148 proved to be indifferently potent against wild-type, ΔdltA and ΔmprF S. aureus strains. When used alone, relatively high concentrations of both LL-37 and teicoplanin (30–120 µM and 4–32 mg/L, respectively) were required to kill S. aureus. Resistance to LL-37 in S. aureus was overcome by combined use of teicoplanin and LL-37. Thus, teicoplanin potentiates peptide LL-37, enhancing the efficacy of the innate defence, and combining the novel peptides with teicoplanin offers potential for enhanced efficacy of treatment of S. aureus infections, including biofilms. 相似文献
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