Cationic host defense peptides; novel antimicrobial therapeutics against Category A pathogens and emerging infections

Findlay, Fern; Proudfoot, Lorna; Stevens, Craig; Barlow, Peter G.

doi:10.1080/20477724.2016.1195036

Cited by 36 publications

(32 citation statements)

References 124 publications

(119 reference statements)

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“…Host defense peptides (HDP) are promising antibacterial compounds considered to be promising candidates due to their broad range of activity and multiple mechanism of action [9][10][11] which leads to less resistance developed by the bacteria so HDP are new popular topic for research all over the world [12][13][14]. The broad spectrum of HDP makes them suitable for future medical applications; in this sense, nanotechnology provides promising support for peptide transport and targeted delivery with strongly enhanced biocidal properties and significant reduction of toxicity [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Nano-encapsulated HHC10 host defense peptide (HDP) reduces the growth of Escherichia coli via multimodal mechanisms

Sharma

Vaghasiya

Ray

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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The eradication of several pathogenic drug resistant "Superbug" such as Escherichia coli became difficult especially in chronic infections using existing antibiotics due to the emergence of antibiotic resistance. Owing to their unique antibacterial properties, host defense peptides (HDP) have gained significant attention to combat colonization of bacteria. This study aims designing delivery systems for HHC10 peptide to target bacteria inside the cells might be a promising approach by protecting from degradation, controlling the release, enhancing the susceptibility of target microbes and improving bioavailability. Nano-formulated HHC10 was evaluated for its efficacy (CFU assay) and possible mechanism of action (membrane interaction and apoptosis) against E. coli. Dose-dependent inhibition of E. coli growth is observed for nano-encapsulated and bare HHC10 and encapsulated form remain non-toxic to macrophage mouse cells (RAW264.6) up to 20 μM. Mechanistic analyses using transmission electron microscopy and flow cytometry techniques revealed that bactericidal activity of HHC10-NP progresses via a multimodal mechanism of bacterial cell death by cell-membrane lysis on direct interaction with bacteria while through induction of the apoptotic death pathway inside the host cells. These results offer an insight on future strategies for the development and application of antimicrobial peptides as antibacterial alternatives. [Formula: see text] Controlled delivery of HHC10 peptide from PLGA-NP kills bacteria by two different mechanism: (i) direct killing: HHC10 disintegrate the cell membrane of bacteria by electrostatic interactions and (ii) indirect killing: induction of apoptosis in bacteria infect cells.

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Section: Introductionmentioning

confidence: 99%

Nano-encapsulated HHC10 host defense peptide (HDP) reduces the growth of Escherichia coli via multimodal mechanisms

Sharma

Vaghasiya

Ray

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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“…1–3 Thus, there is an emerging interest in developing CAPs for therapeutic applications, including the development of novel antibiotics, anti-fungal agents and anticancer drugs. 4,5 In relation to the potential use of CAPs in anticancer therapy, CAPs make attractive candidates because of a number of unique properties that distinguish them from traditional chemotherapy options. For example, CAPs often display high selectivity for tumor cells compared with normal cells because of the higher negative cell surface charge of many tumor cells, 6,7 whereas their nonselectivity for rapidly dividing cells, unlike most chemotherapeutics, means they have the potential to target both active and dormant tumors.…”

Section: Introductionmentioning

confidence: 99%

The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process

2017

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Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6–24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway.

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“…Two major families have been characterized in humans, defensins and cathelicidins, and peptides from both families have been demonstrated to possess potent immunomodulatory and antimicrobial activities (reviewed in Refs. [5][6][7]. These peptides are regarded as key elements of the innate immune system.…”

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confidence: 99%

Carbon Nanoparticles Inhibit the Antimicrobial Activities of the Human Cathelicidin LL-37 through Structural Alteration

Findlay

Pohl

Svoboda

et al. 2017

The Journal of Immunology

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Host defense peptides, also known as antimicrobial peptides, are key elements of innate host defense. One host defense peptide with well-characterized antimicrobial activity is the human cathelicidin, LL-37. LL-37 has been shown to be upregulated at sites of infection and inflammation and is regarded as one of the primary innate defense molecules against bacterial and viral infection. Human exposure to combustion-derived or engineered nanoparticles is of increasing concern, and the implications of nanomaterial exposure on the human immune response is poorly understood. However, it is widely acknowledged that nanoparticles can interact strongly with several immune proteins of biological significance, with these interactions resulting in structural and functional changes of the proteins involved. This study investigated whether the potent antibacterial and antiviral functions of LL-37 were inhibited by exposure to, and interaction with, carbon nanoparticles, together with characterizing the nature of the interaction. LL-37 was exposed to carbon black nanoparticles in vitro, and the antibacterial and antiviral functions of the peptide were subsequently assessed. We demonstrate a substantial loss of antimicrobial function when the peptide was exposed to low concentrations of nanomaterials, and we further show that the nanomaterial-peptide interaction resulted in a significant change in the structure of the peptide. The human health implications of these findings are significant, as, to our knowledge, this is the first evidence that nanoparticles can alter host defense peptide structure and function, indicating a new role for nanoparticle exposure in increased disease susceptibility.

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Cationic host defense peptides; novel antimicrobial therapeutics against Category A pathogens and emerging infections

Cited by 36 publications

References 124 publications

Nano-encapsulated HHC10 host defense peptide (HDP) reduces the growth of Escherichia coli via multimodal mechanisms

Nano-encapsulated HHC10 host defense peptide (HDP) reduces the growth of Escherichia coli via multimodal mechanisms

The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process

Carbon Nanoparticles Inhibit the Antimicrobial Activities of the Human Cathelicidin LL-37 through Structural Alteration

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