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Open AccessArticle

pMPES: A Modular Peptide Expression System for the Delivery of Antimicrobial Peptides to the Site of Gastrointestinal Infections Using Probiotics

by Kathryn Geldart, Brittany Forkus, Evelyn McChesney, Madeline McCue and Yiannis N. Kaznessis

Pharmaceuticals 2016, 9(4), 60; https://doi.org/10.3390/ph9040060 - 5 Oct 2016

Cited by 24 | Viewed by 7764

Abstract

Antimicrobial peptides are a promising alternative to traditional antibiotics, but their utility is limited by high production costs and poor bioavailability proﬁles. Bacterial production and delivery of antimicrobial peptides (AMPs) directly at the site of infection may offer a path for effective therapeutic [...] Read more.

Antimicrobial peptides are a promising alternative to traditional antibiotics, but their utility is limited by high production costs and poor bioavailability proﬁles. Bacterial production and delivery of antimicrobial peptides (AMPs) directly at the site of infection may offer a path for effective therapeutic application. In this study, we have developed a vector that can be used for the production and secretion of seven antimicrobial peptides from both Escherichia coli MC1061 F’ and probiotic E.coli Nissle 1917. The vector pMPES (Modular Peptide Expression System) employs the Microcin V (MccV) secretion system and a powerful synthetic promoter to drive AMP production. Herein, we demonstrate the capacity of pMPES to produce inhibitory levels of MccV, Microcin L (MccL), Microcin N (McnN), Enterocin A (EntA), Enterocin P (EntP), Hiracin JM79 (HirJM79) and Enterocin B (EntB). To our knowledge, this is the ﬁrst demonstration of such a broadly-applicable secretion system for AMP production. This type of modular expression system could expedite the development of sorely needed antimicrobial technologies Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessArticle

Therapeutic Potential of Gramicidin S in the Treatment of Root Canal Infections

by Marina Berditsch, Hannah Lux, Oleg Babii, Sergii Afonin and Anne S. Ulrich

Pharmaceuticals 2016, 9(3), 56; https://doi.org/10.3390/ph9030056 - 7 Sep 2016

Cited by 30 | Viewed by 6918

Abstract

An intrinsic clindamycin-resistant Enterococcus faecalis, the most common single species present in teeth after failed root canal therapy, often possesses acquired tetracycline resistance. In these cases, root canal infections are commonly treated with Ledermix^® paste, which contains demeclocycline, or the new [...] Read more.

An intrinsic clindamycin-resistant Enterococcus faecalis, the most common single species present in teeth after failed root canal therapy, often possesses acquired tetracycline resistance. In these cases, root canal infections are commonly treated with Ledermix^® paste, which contains demeclocycline, or the new alternative endodontic paste Odontopaste, which contains clindamycin; however, these treatments are often ineffective. We studied the killing activity of the cyclic antimicrobial peptide gramicidin S (GS) against planktonic and biofilm cells of tetracycline-resistant clinical isolates of E. faecalis. The high therapeutic potential of GS for the topical treatment of problematic teeth is based on the rapid bactericidal effect toward the biofilm-forming, tetracycline-resistant E. faecalis. GS reduces the cell number of planktonic cells within 20–40 min at a concentration of 40–80 μg/mL. It kills the cells of pre-grown biofilms at concentrations of 100–200 μg/mL, such that no re-growth is possible. The translocation of the peptide into the cell interior and its complexation with intracellular nucleotides, including the alarmon ppGpp, can explain its anti-biofilm effect. The successful treatment of persistently infected root canals of two volunteers confirms the high effectiveness of GS. The broad GS activity towards resistant, biofilm-forming E. faecalis suggests its applications for approval in root canal medication. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Review

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Open AccessReview

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

by Erum Malik, Sarah R. Dennison, Frederick Harris and David A. Phoenix

Pharmaceuticals 2016, 9(4), 67; https://doi.org/10.3390/ph9040067 - 1 Nov 2016

Cited by 97 | Viewed by 10500

Abstract

Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that [...] Read more.

Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessReview

Antimicrobial Peptides Targeting Gram-Positive Bacteria

by Nermina Malanovic and Karl Lohner

Pharmaceuticals 2016, 9(3), 59; https://doi.org/10.3390/ph9030059 - 20 Sep 2016

Cited by 301 | Viewed by 19091

Abstract

Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential [...] Read more.

Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential to consider the architecture of their cell envelopes. Before AMPs can interact with the cytoplasmic membrane of Gram-positive bacteria, they have to traverse the cell wall composed of wall- and lipoteichoic acids and peptidoglycan. While interaction of AMPs with peptidoglycan might rather facilitate penetration, interaction with anionic teichoic acids may act as either a trap for AMPs or a ladder for a route to the cytoplasmic membrane. Interaction with the cytoplasmic membrane frequently leads to lipid segregation affecting membrane domain organization, which affects membrane permeability, inhibits cell division processes or leads to delocalization of essential peripheral membrane proteins. Further, precursors of cell wall components, especially the highly conserved lipid II, are directly targeted by AMPs. Thereby, the peptides do not inhibit peptidoglycan synthesis via binding to proteins like common antibiotics, but form a complex with the precursor molecule, which in addition can promote pore formation and membrane disruption. Thus, the multifaceted mode of actions will make AMPs superior to antibiotics that act only on one specific target. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessReview

The Role of Antimicrobial Peptides in Influenza Virus Infection and Their Potential as Antiviral and Immunomodulatory Therapy

by I-Ni Hsieh and Kevan L. Hartshorn

Pharmaceuticals 2016, 9(3), 53; https://doi.org/10.3390/ph9030053 - 6 Sep 2016

Cited by 69 | Viewed by 8278

Abstract

Influenza A virus (IAV) remains a major threat that can cause severe morbidity and mortality due to rapid genomic variation. Resistance of IAVs to current anti-IAV drugs has been emerging, and antimicrobial peptides (AMPs) have been considered to be potential candidates for novel [...] Read more.

Influenza A virus (IAV) remains a major threat that can cause severe morbidity and mortality due to rapid genomic variation. Resistance of IAVs to current anti-IAV drugs has been emerging, and antimicrobial peptides (AMPs) have been considered to be potential candidates for novel treatment against IAV infection. AMPs are endogenous proteins playing important roles in host defense through direct antimicrobial and antiviral activities and through immunomodulatory effects. In this review, we will discuss the anti-IAV and immunomodulatory effects of classical AMPs (defensins and cathelicidins), and proteins more recently discovered to have AMP-like activity (histones and Alzheimer’s associated β-amyloid). We will discuss the interactions between AMPs and other host defense proteins. Major emphasis will be placed on novel synthetic AMPs derived from modification of natural proteins, and on potential methods of increasing expression of endogenous AMPs, since these approaches may lead to novel antiviral therapeutics. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessReview

Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP)

by Louise Bjerkan, Andreas Sonesson and Karl Schenck

Pharmaceuticals 2016, 9(3), 41; https://doi.org/10.3390/ph9030041 - 5 Jul 2016

Cited by 30 | Viewed by 9564

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, hitherto mostly known to be involved in inflammatory responses and immunoregulation. The human tslp gene gives rise to two transcription and translation variants: a long form (lfTSLP) that is induced by inflammation, and a short, [...] Read more.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, hitherto mostly known to be involved in inflammatory responses and immunoregulation. The human tslp gene gives rise to two transcription and translation variants: a long form (lfTSLP) that is induced by inflammation, and a short, constitutively-expressed form (sfTSLP), that appears to be downregulated by inflammation. The TSLP forms can be produced by a number of cell types, including epithelial and dendritic cells (DCs). lfTSLP can activate mast cells, DCs, and T cells through binding to the lfTSLP receptor (TSLPR) and has a pro-inflammatory function. In contrast, sfTSLP inhibits cytokine secretion of DCs, but the receptor mediating this effect is unknown. Our recent studies have demonstrated that both forms of TSLP display potent antimicrobial activity, exceeding that of many other known antimicrobial peptides (AMPs), with sfTSLP having the strongest effect. The AMP activity is primarily mediated by the C-terminal region of the protein and is localized within a 34-mer peptide (MKK34) that spans the C-terminal α-helical region in TSLP. Fluorescent studies of peptide-treated bacteria, electron microscopy, and liposome leakage models showed that MKK34 exerted membrane-disrupting effects comparable to those of LL-37. Expression of TSLP in skin, oral mucosa, salivary glands, and intestine is part of the defense barrier that aids in the control of both commensal and pathogenic microbes. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessReview

Functions of Cationic Host Defense Peptides in Immunity

by Mahadevappa Hemshekhar, Vidyanand Anaparti and Neeloffer Mookherjee

Pharmaceuticals 2016, 9(3), 40; https://doi.org/10.3390/ph9030040 - 4 Jul 2016

Cited by 71 | Viewed by 6685

Abstract

Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique [...] Read more.

Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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Open AccessReview

Potential Use of Antimicrobial Peptides as Vaginal Spermicides/Microbicides

by Nongnuj Tanphaichitr, Nopparat Srakaew, Rhea Alonzi, Wongsakorn Kiattiburut, Kessiri Kongmanas, Ruina Zhi, Weihua Li, Mark Baker, Guanshun Wang and Duane Hickling

Pharmaceuticals 2016, 9(1), 13; https://doi.org/10.3390/ph9010013 - 11 Mar 2016

Cited by 43 | Viewed by 13696

Abstract

The concurrent increases in global population and sexually transmitted infection (STI) demand a search for agents with dual spermicidal and microbicidal properties for topical vaginal application. Previous attempts to develop the surfactant spermicide, nonoxynol-9 (N-9), into a vaginal microbicide were unsuccessful largely due [...] Read more.

The concurrent increases in global population and sexually transmitted infection (STI) demand a search for agents with dual spermicidal and microbicidal properties for topical vaginal application. Previous attempts to develop the surfactant spermicide, nonoxynol-9 (N-9), into a vaginal microbicide were unsuccessful largely due to its inefficiency to kill microbes. Furthermore, N-9 causes damage to the vaginal epithelium, thus accelerating microbes to enter the women’s body. For this reason, antimicrobial peptides (AMPs), naturally secreted by all forms of life as part of innate immunity, deserve evaluation for their potential spermicidal effects. To date, twelve spermicidal AMPs have been described including LL-37, magainin 2 and nisin A. Human cathelicidin LL-37 is the most promising spermicidal AMP to be further developed for vaginal use for the following reasons. First, it is a human AMP naturally produced in the vagina after intercourse. Second, LL-37 exerts microbicidal effects to numerous microbes including those that cause STI. Third, its cytotoxicity is selective to sperm and not to the female reproductive tract. Furthermore, the spermicidal effects of LL-37 have been demonstrated in vivo in mice. Therefore, the availability of LL-37 as a vaginal spermicide/microbicide will empower women for self-protection against unwanted pregnancies and STI. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Expanded Activity Spectrum and Applications)

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