Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts

Benincasa, Monica; Scocchi, Marco; Pacor, Sabrina; Tossi, Alessandro; Nobili, Donatella; Basaglia, Giancarlo; Busetti, Marina; Gennaro, Renato

doi:10.1093/jac/dkl382

Cited by 127 publications

(100 citation statements)

References 44 publications

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“…The antifungal activity of LL-37 and BMAP-28 has been reported previously (22,27). The activity of all five peptides was examined against two agronomically important fungal pathogens, F. oxysporum f. sp.…”

Section: Discussionmentioning

confidence: 85%

Permeabilization of Fungal Hyphae by the Plant Defensin NaD1 Occurs through a Cell Wall-dependent Process

Weerden

Hancock

Anderson

2010

Journal of Biological Chemistry

161

130

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The antifungal activity of the plant defensin NaD1 involves specific interaction with the fungal cell wall, followed by permeabilization of the plasma membrane and entry of NaD1 into the cytoplasm. Prior to this study, the role of membrane permeabilization in the activity of NaD1, as well as the relevance of cell wall binding, had not been investigated. To address this, the permeabilization of Fusarium oxysporum f. sp. vasinfectum hyphae by NaD1 was investigated and compared with that by other antimicrobial peptides, including the cecropin-melittin hybrid peptide CP-29, the bovine peptide BMAP-28, and the human peptide LL-37, which are believed to act largely through membrane disruption. NaD1 appeared to permeabilize cells via a novel mechanism that required the presence of the fungal cell wall. NaD1 and Bac2A, a linear variant of the bovine peptide bactenecin, were able to enter the cytoplasm of treated hyphae, indicating that cell death is accelerated by interaction with intracellular targets.Peptides with the ability to kill microbes are found ubiquitously throughout nature. The Antimicrobial Peptide Database (1) currently lists 1528 peptides from a diverse range of sources, including bacteria, fungi, fish, amphibians, spiders, mammals, and plants. Despite a number of common characteristics such as their small size and net positive charge, the mechanism of action for these peptides varies significantly. One common feature is their ability to permeabilize the plasma membrane of target cells. Initially, this permeabilization event was believed to be the sole event responsible for cell killing. Although this may be true for some peptides, it is now clear that other peptides may permeabilize membranes to access the cytoplasm and interact with intracellular targets (reviewed in Ref. 2).Plants produce a number of cysteine-rich cationic peptides for protection against infection by potential microbial pathogens. Defensins are one such group of peptides and are one of the largest families of antimicrobial peptides in plants. Plant defensins are small (45-54 amino acids) basic proteins with four to five disulfide bonds (3). They share structural and functional similarities with defensins from insects (4), mammals (5), and fungi (6). A variety of functions have been attributed to plant defensins, including antibacterial activity (7, 8), protein synthesis inhibition (9), and inhibition of ␣-amylases and proteases (10 -12). A large proportion of plant defensins display antifungal activity. NaD1 (Nicotiana alata defensin 1) is expressed at high concentrations in the flowers of the ornamental tobacco N. alata (13). It targets filamentous fungi and appears to act via a three-step process that begins with interaction with the fungal cell wall, followed by permeabilization of the plasma membrane and subsequent entry of the defensin into the cytoplasm (14).Two groups of models have been proposed to explain how peptides interact with and disrupt membranes. The first, known as the barrel-stave model, involves the formation of dis...

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Section: Discussionmentioning

confidence: 85%

Permeabilization of Fungal Hyphae by the Plant Defensin NaD1 Occurs through a Cell Wall-dependent Process

Weerden

Hancock

Anderson

2010

Journal of Biological Chemistry

161

130

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“…However, C. glabrata has been shown to be scarcely susceptible to a wide spectrum of AMPs of different derivations; among these are histatin, cathelicidins, defensins, and magainin (7)(8)(9)(10).…”

mentioning

confidence: 99%

Antifungal Activity of the Noncytotoxic Human Peptide Hepcidin 20 against Fluconazole-Resistant Candida glabrata in Human Vaginal Fluid

Gaudio

Lombardi

Maisetta

et al. 2013

Antimicrob Agents Chemother

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“…Numerous studies have suggested that naturally occurring host defense peptides (30)(31)(32)(33)(34) and synthetic derivatives of these peptides (35-37) could be useful drugs to treat fungal infections, including those caused by Candida pathogens. Since Candida spp.…”

Section: Discussionmentioning

confidence: 99%

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

Ryan

Freeman

Masso-Silva

et al. 2014

Antimicrob Agents Chemother

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There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.

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Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts

Cited by 127 publications

References 44 publications

Permeabilization of Fungal Hyphae by the Plant Defensin NaD1 Occurs through a Cell Wall-dependent Process

Permeabilization of Fungal Hyphae by the Plant Defensin NaD1 Occurs through a Cell Wall-dependent Process

Antifungal Activity of the Noncytotoxic Human Peptide Hepcidin 20 against Fluconazole-Resistant Candida glabrata in Human Vaginal Fluid

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

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