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Antimicrobial peptides: primeval molecules or future drugs?

Peters BM, Shirtliff ME, Jabra-Rizk MA - PLoS Pathog. (2010)

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Life Sciences, Microbiology and Immunology Program, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.

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However, our bodies are equipped with an evolutionarily conserved innate immune defense system that allows us to thwart potential pathogens... Antimicrobial peptides (AMPs) are a unique and assorted group of molecules produced by living organisms of all types, considered to be part of the host innate immunity, ... The molecular mechanism and pathway of membrane permeation may vary for different peptides depending on a number of parameters, such as the amino acid sequence, membrane lipid composition, and peptide concentration... Although the mechanisms by which peptides associate with and permeabilize microbial cell membranes are not entirely clear, AMPs are proposed to bind to the cytoplasmic membrane, creating micelle-like aggregates, leading to a disruptive effect (Figure 2)... AMPs have a number of potential advantages as future therapeutics; in addition to their broad spectrum antimicrobial activity and rapid killing of microbes, they neutralize endotoxin and are unaffected by classical antibiotic resistance mechanisms, ,... Significantly, given their proclivity to permeabilize target microbial membranes, the most promising potential application for AMPs is for enhancement of the potency of existing antimicrobials by facilitating access into the microbial cell, resulting in synergistic therapeutic effects, ... Moreover, unlike conventional antibiotics, which microbes readily circumvent, AMPs do not appear to induce antibiotic resistance, most likely due to the profound changes in membrane structure warranted to confer the microbial cell with resistance... Nevertheless, microbial pathogens have the capabilities to coordinate countermeasures to circumvent antimicrobial peptide targeting and evade host immune defenses, ,... The newly identified mechanism of immune evasion employed by the pathogenic fungal species Candida albicans, the etiologic agent of oral candidiasis (thrush), serves as a good example of microbial strategies to thwart the deleterious effects of AMPs... The salivary antimicrobial peptide histatin-5 exhibits potent anti-candidal properties and therefore is considered to be important in protecting the oral cavity against candidiasis... However, recently C. albicans was described to be capable of cleaving histatin-5 not only at specific amino acid residues required for successful intracellular uptake of histatin-5, but also at sites located within the antimicrobial fragment of histatin-5, resulting in deactivation of its anti-candidal potency... Nevertheless, future research aimed at broadening our understanding of the mechanisms used by both host and microbe will undoubtedly lead to new therapeutic options for managing resistant microbial infections... This is evident by the increasing number of studies to which these peptides are subjected... As our need for new antimicrobials becomes more pressing, the question remains: can we develop novel drugs based on the design principles of primitive molecules?

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The proposed diverse mechanistic modes of action for antimicrobial peptides in microbial cells.(A) Disruption of cell membrane integrity: (1) random insertion into the membrane, (2) alignment of hydrophobic sequences, and (3) removal of membrane sections and formation of pores. (B) Inhibition of DNA synthesis. (C) Blocking of RNA synthesis. (D) Inhibition of enzymes necessary for linking of cell wall structural proteins. (E) Inhibition of ribosomal function and protein synthesis. (F) Blocking of chaperone proteins necessary for proper folding of proteins. (G) Targeting of mitochondria: (1) inhibition of cellular respiration and induction of ROS formation and (2) disruption of mitochondrial cell membrane integrity and efflux of ATP and NADH.
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ppat-1001067-g002: The proposed diverse mechanistic modes of action for antimicrobial peptides in microbial cells.(A) Disruption of cell membrane integrity: (1) random insertion into the membrane, (2) alignment of hydrophobic sequences, and (3) removal of membrane sections and formation of pores. (B) Inhibition of DNA synthesis. (C) Blocking of RNA synthesis. (D) Inhibition of enzymes necessary for linking of cell wall structural proteins. (E) Inhibition of ribosomal function and protein synthesis. (F) Blocking of chaperone proteins necessary for proper folding of proteins. (G) Targeting of mitochondria: (1) inhibition of cellular respiration and induction of ROS formation and (2) disruption of mitochondrial cell membrane integrity and efflux of ATP and NADH.

Mentions: Despite their vast diversity, most AMPs work directly against microbes through a mechanism involving membrane disruption and pore formation, allowing efflux of essential ions and nutrients. The molecular mechanism and pathway of membrane permeation may vary for different peptides depending on a number of parameters, such as the amino acid sequence, membrane lipid composition, and peptide concentration [3]. Although the mechanisms by which peptides associate with and permeabilize microbial cell membranes are not entirely clear, AMPs are proposed to bind to the cytoplasmic membrane, creating micelle-like aggregates, leading to a disruptive effect (Figure 2). However, a mounting body of evidence indicates the presence of additional or complementary mechanisms such as intracellular targeting of cytoplasmic components crucial to proper cellular physiology (Figure 2) [7], [8]. Thus, the initial interaction between the peptides and the microbial cell membrane would allow them to penetrate into the cell to bind intracellular molecules, resulting in the inhibition of cell wall biosynthesis and DNA, RNA, and protein synthesis. AMPs also possess anti-viral properties, inhibiting viral fusion and egress, thus preventing infection and viral spread via direct interactions with the membranous viral envelope and host cell surface molecules. These properties, combined with the broad range of activity and the short contact time required to induce killing, have led to the consideration of AMPs as excellent candidates for development as novel therapeutic agents. Therefore, insights into the mechanisms employed by AMPs will facilitate new approaches to discover and develop pharmacologic agents.


Antimicrobial peptides: primeval molecules or future drugs?

Peters BM, Shirtliff ME, Jabra-Rizk MA - PLoS Pathog. (2010)

The proposed diverse mechanistic modes of action for antimicrobial peptides in microbial cells.(A) Disruption of cell membrane integrity: (1) random insertion into the membrane, (2) alignment of hydrophobic sequences, and (3) removal of membrane sections and formation of pores. (B) Inhibition of DNA synthesis. (C) Blocking of RNA synthesis. (D) Inhibition of enzymes necessary for linking of cell wall structural proteins. (E) Inhibition of ribosomal function and protein synthesis. (F) Blocking of chaperone proteins necessary for proper folding of proteins. (G) Targeting of mitochondria: (1) inhibition of cellular respiration and induction of ROS formation and (2) disruption of mitochondrial cell membrane integrity and efflux of ATP and NADH.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2965748&req=5

ppat-1001067-g002: The proposed diverse mechanistic modes of action for antimicrobial peptides in microbial cells.(A) Disruption of cell membrane integrity: (1) random insertion into the membrane, (2) alignment of hydrophobic sequences, and (3) removal of membrane sections and formation of pores. (B) Inhibition of DNA synthesis. (C) Blocking of RNA synthesis. (D) Inhibition of enzymes necessary for linking of cell wall structural proteins. (E) Inhibition of ribosomal function and protein synthesis. (F) Blocking of chaperone proteins necessary for proper folding of proteins. (G) Targeting of mitochondria: (1) inhibition of cellular respiration and induction of ROS formation and (2) disruption of mitochondrial cell membrane integrity and efflux of ATP and NADH.
Mentions: Despite their vast diversity, most AMPs work directly against microbes through a mechanism involving membrane disruption and pore formation, allowing efflux of essential ions and nutrients. The molecular mechanism and pathway of membrane permeation may vary for different peptides depending on a number of parameters, such as the amino acid sequence, membrane lipid composition, and peptide concentration [3]. Although the mechanisms by which peptides associate with and permeabilize microbial cell membranes are not entirely clear, AMPs are proposed to bind to the cytoplasmic membrane, creating micelle-like aggregates, leading to a disruptive effect (Figure 2). However, a mounting body of evidence indicates the presence of additional or complementary mechanisms such as intracellular targeting of cytoplasmic components crucial to proper cellular physiology (Figure 2) [7], [8]. Thus, the initial interaction between the peptides and the microbial cell membrane would allow them to penetrate into the cell to bind intracellular molecules, resulting in the inhibition of cell wall biosynthesis and DNA, RNA, and protein synthesis. AMPs also possess anti-viral properties, inhibiting viral fusion and egress, thus preventing infection and viral spread via direct interactions with the membranous viral envelope and host cell surface molecules. These properties, combined with the broad range of activity and the short contact time required to induce killing, have led to the consideration of AMPs as excellent candidates for development as novel therapeutic agents. Therefore, insights into the mechanisms employed by AMPs will facilitate new approaches to discover and develop pharmacologic agents.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Life Sciences, Microbiology and Immunology Program, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

However, our bodies are equipped with an evolutionarily conserved innate immune defense system that allows us to thwart potential pathogens... Antimicrobial peptides (AMPs) are a unique and assorted group of molecules produced by living organisms of all types, considered to be part of the host innate immunity, ... The molecular mechanism and pathway of membrane permeation may vary for different peptides depending on a number of parameters, such as the amino acid sequence, membrane lipid composition, and peptide concentration... Although the mechanisms by which peptides associate with and permeabilize microbial cell membranes are not entirely clear, AMPs are proposed to bind to the cytoplasmic membrane, creating micelle-like aggregates, leading to a disruptive effect (Figure 2)... AMPs have a number of potential advantages as future therapeutics; in addition to their broad spectrum antimicrobial activity and rapid killing of microbes, they neutralize endotoxin and are unaffected by classical antibiotic resistance mechanisms, ,... Significantly, given their proclivity to permeabilize target microbial membranes, the most promising potential application for AMPs is for enhancement of the potency of existing antimicrobials by facilitating access into the microbial cell, resulting in synergistic therapeutic effects, ... Moreover, unlike conventional antibiotics, which microbes readily circumvent, AMPs do not appear to induce antibiotic resistance, most likely due to the profound changes in membrane structure warranted to confer the microbial cell with resistance... Nevertheless, microbial pathogens have the capabilities to coordinate countermeasures to circumvent antimicrobial peptide targeting and evade host immune defenses, ,... The newly identified mechanism of immune evasion employed by the pathogenic fungal species Candida albicans, the etiologic agent of oral candidiasis (thrush), serves as a good example of microbial strategies to thwart the deleterious effects of AMPs... The salivary antimicrobial peptide histatin-5 exhibits potent anti-candidal properties and therefore is considered to be important in protecting the oral cavity against candidiasis... However, recently C. albicans was described to be capable of cleaving histatin-5 not only at specific amino acid residues required for successful intracellular uptake of histatin-5, but also at sites located within the antimicrobial fragment of histatin-5, resulting in deactivation of its anti-candidal potency... Nevertheless, future research aimed at broadening our understanding of the mechanisms used by both host and microbe will undoubtedly lead to new therapeutic options for managing resistant microbial infections... This is evident by the increasing number of studies to which these peptides are subjected... As our need for new antimicrobials becomes more pressing, the question remains: can we develop novel drugs based on the design principles of primitive molecules?

Show MeSH
Related in: MedlinePlus