Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies.
TL;DR: The role of cationic host-defense peptides in modulating the innate immune response and boosting infection-resolving immunity while dampening potentially harmful pro-inflammatory (septic) responses gives these peptides the potential to become an entirely new therapeutic approach against bacterial infections.
Abstract: Short cationic amphiphilic peptides with antimicrobial and/or immunomodulatory activities are present in virtually every life form, as an important component of (innate) immune defenses. These host-defense peptides provide a template for two separate classes of antimicrobial drugs. Direct-acting antimicrobial host-defense peptides can be rapid-acting and potent, and possess an unusually broad spectrum of activity; consequently, they have prospects as new antibiotics, although clinical trials to date have shown efficacy only as topical agents. But for these compounds to fulfill their therapeutic promise and overcome clinical setbacks, further work is needed to understand their mechanisms of action and reduce the potential for unwanted toxicity, to make them more resistant to protease degradation and improve serum half-life, as well as to devise means of manufacturing them on a large scale in a consistent and cost-effective manner. In contrast, the role of cationic host-defense peptides in modulating the innate immune response and boosting infection-resolving immunity while dampening potentially harmful pro-inflammatory (septic) responses gives these peptides the potential to become an entirely new therapeutic approach against bacterial infections.
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TL;DR: The aim of broth and agar dilution methods is to determine the lowest concentration of the assayed antimicrobial agent (minimal inhibitory concentration, MIC) that, under defined test conditions, inhibits the visible growth of the bacterium being investigated.
Abstract: The aim of broth and agar dilution methods is to determine the lowest concentration of the assayed antimicrobial agent (minimal inhibitory concentration, MIC) that, under defined test conditions, inhibits the visible growth of the bacterium being investigated. MIC values are used to determine susceptibilities of bacteria to drugs and also to evaluate the activity of new antimicrobial agents. Agar dilution involves the incorporation of different concentrations of the antimicrobial substance into a nutrient agar medium followed by the application of a standardized number of cells to the surface of the agar plate. For broth dilution, often determined in 96-well microtiter plate format, bacteria are inoculated into a liquid growth medium in the presence of different concentrations of an antimicrobial agent. Growth is assessed after incubation for a defined period of time (16-20 h) and the MIC value is read. This protocol applies only to aerobic bacteria and can be completed in 3 d.
4,223 citations
Cites background from "Antimicrobial and host-defense pept..."
...Please note however that cation-adjusted MHB should not be used when testing the activity of cationic antimicrobial peptides, as the presence of Ca 2+ and Mg 2+ ions causes a substantial inhibition of the cationic peptides' activit...
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Princeton University1, Public Health Foundation of India2, Center for Disease Dynamics, Economics & Policy3, University of the Witwatersrand4, Aga Khan University5, University of Oxford6, Food and Drug Administration7, Institute of Tropical Medicine Antwerp8, Aberdeen Royal Infirmary9, University of Antwerp10, National Veterinary Institute11, Duke University12, Karolinska Institutet13, St. John's University of Tanzania14, University of Cuenca15, Wellcome Trust16, St George's, University of London17, McMaster University18, Uppsala University19
TL;DR: The global situation of antibiotic resistance, its major causes and consequences, and key areas in which action is urgently needed are described and identified.
Abstract: The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.
3,181 citations
TL;DR: The multilayered effects of drug–target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing are discussed.
Abstract: Antibiotic drug-target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug-target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
1,796 citations
Cites background from "Antimicrobial and host-defense pept..."
...Antimicrobial peptides are short cationic peptides that are thought to kill through interactions with the membrane that result in pore formatio...
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TL;DR: In this article, advanced computer assisted design strategies that address the difficult problem of relating primary sequence to peptide structure, and are delivering more potent, cost-effective, broad-spectrum peptides as potential next-generation antibiotics.
Abstract: Multidrug-resistant bacteria are a severe threat to public health. Conventional antibiotics are becoming increasingly ineffective as a result of resistance, and it is imperative to find new antibacterial strategies. Natural antimicrobials, known as host defence peptides or antimicrobial peptides, defend host organisms against microbes but most have modest direct antibiotic activity. Enhanced variants have been developed using straightforward design and optimization strategies and are being tested clinically. Here, we describe advanced computer-assisted design strategies that address the difficult problem of relating primary sequence to peptide structure, and are delivering more potent, cost-effective, broad-spectrum peptides as potential next-generation antibiotics.
1,543 citations
Additional excerpts
...jpg"/> Antimicrobial peptides (AMPs) are produced by multicellular organisms as a defence mechanism against competing pathogenic microbe...
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TL;DR: Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties and various database applications in research and education are summarized.
Abstract: The antimicrobial peptide database (APD, http://aps.unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti-HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, molecule-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education.
1,391 citations
References
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TL;DR: As the need for new antibiotics becomes more pressing, could the design of anti-infective drugs based on the design principles these molecules teach us?
Abstract: Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?
7,657 citations
"Antimicrobial and host-defense pept..." refers background in this paper
...dtd" [ ]> Short cationic amphiphilic peptides are present in virtually every life form as Nature's antibiotic...
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TL;DR: The intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.
Abstract: Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are observed among peptides of widely diverse source and composition. Biochemical distinctions among the peptides themselves, target versus host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.
2,687 citations
"Antimicrobial and host-defense pept..." refers background in this paper
...Indeed, the action of many peptides cannot be explained by disruption of membrane permeability barriers, as discussed in several review...
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Patent•
14 Jun 1999
TL;DR: In this paper, a high throughput screen for determining the effect of test compounds on ion channel or transporter activity was proposed, and a method for monitoring ion channel activity in a membrane.
Abstract: The present invention relates to a structure comprising a biological membrane and a porous or perforated substrate, a biological membrane, a substrate, a high throughput screen, methods for production of the structure membrane and substrate, and a method for screening a large number of test compounds in a short period. More particularly it relates to a structure comprising a biological membrane adhered to a porous or perforated substrate, a biological membrane capable of adhering with high resistance seals to a substrate such as perforated glass and the ability to form sheets having predominantly an ion channel or transporter of interest, a high throughput screen for determining the effect of test compounds on ion channel or transporter activity, methods for manufacture of the structure, membrane and substrate, and a method for monitoring ion channel or transporter activity in a membrane.
2,232 citations
TL;DR: 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.
Abstract: 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.
2,231 citations
"Antimicrobial and host-defense pept..." refers background in this paper
...Several complex and controversial models describe these subsequent events, including the reorientation of peptide molecules perpendicular to the membrane to form either barrel-stave or toroidal channels, the breakdown of membrane integrity as a result of the swamping of membrane charge by a 'carpet' of peptides at the interface, the detergent-like dissolution of patches of membrane and the formation of peptide-lipid aggregates within the bilaye...
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TL;DR: Bacteriocins are bacterially produced antimicrobial peptides with narrow or broad host ranges that can be used to confer a rudimentary form of innate immunity to foodstuffs, helping processors extend their control over the food flora long after manufacture.
Abstract: Bacteriocins are bacterially produced antimicrobial peptides with narrow or broad host ranges. Many bacteriocins are produced by food-grade lactic acid bacteria, a phenomenon which offers food scientists the possibility of directing or preventing the development of specific bacterial species in food. This can be particularly useful in preservation or food safety applications, but also has implications for the development of desirable flora in fermented food. In this sense, bacteriocins can be used to confer a rudimentary form of innate immunity to foodstuffs, helping processors extend their control over the food flora long after manufacture.
2,051 citations