Editorial

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2 pages, 151 KiB

Open AccessEditorial

Antifungal Peptides

by Gill Diamond

J. Fungi 2021, 7(6), 437; https://doi.org/10.3390/jof7060437 - 31 May 2021

Cited by 2 | Viewed by 2059

Abstract

Fungal infections represent an increasing public health crisis [...] Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

Research

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19 pages, 6469 KiB

Open AccessEditor’s ChoiceArticle

In Vitro and In Vivo Anti-Candida Activity and Structural Analysis of Killer Peptide (KP)-Derivatives

by Tecla Ciociola, Thelma A. Pertinhez, Tiziano De Simone, Walter Magliani, Elena Ferrari, Silvana Belletti, Tiziana D’Adda, Stefania Conti and Laura Giovati

J. Fungi 2021, 7(2), 129; https://doi.org/10.3390/jof7020129 - 10 Feb 2021

Cited by 7 | Viewed by 2898

Abstract

The previously described decapeptide AKVTMTCSAS (killer peptide, KP), derived from the variable region of a recombinant yeast killer toxin-like anti-idiotypic antibody, proved to exert a variety of antimicrobial, antiviral, and immunomodulatory activities. It also showed a peculiar self-assembly ability, likely responsible for the [...] Read more.

The previously described decapeptide AKVTMTCSAS (killer peptide, KP), derived from the variable region of a recombinant yeast killer toxin-like anti-idiotypic antibody, proved to exert a variety of antimicrobial, antiviral, and immunomodulatory activities. It also showed a peculiar self-assembly ability, likely responsible for the therapeutic effect in animal models of systemic and mucosal candidiasis. The present study analyzed the biological and structural properties of peptides derived from KP by substitution or deletion of the first residue, leaving unchanged the remaining amino acids. The investigated peptides proved to exert differential in vitro and/or in vivo anti-Candida activity without showing toxic effects on mammalian cells. The change of the first residue in KP amino acidic sequence affected the conformation of the resulting peptides in solution, as assessed by circular dichroism spectroscopy. KP-derivatives, except one, were able to induce apoptosis in yeast cells, like KP itself. ROS production and changes in mitochondrial transmembrane potential were also observed. Confocal and transmission electron microscopy studies allowed to establish that selected peptides could penetrate within C. albicans cells and cause gross morphological alterations. Overall, the physical and chemical properties of the first residue were found to be important for peptide conformation, candidacidal activity and possible mechanism of action. Small antimicrobial peptides could be exploited for the development of a new generation of antifungal drugs, given their relative low cost and ease of production as well as the possibility of devising novel delivery systems. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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12 pages, 5106 KiB

Open AccessArticle

A Novel Immunocompetent Mouse Model for Testing Antifungal Drugs Against Invasive Candida albicans Infection

by Lisa K. Ryan, Amy G Hise, Chowdhury Mobaswar Hossain, William Ruddick, Rezwana Parveen, Katie B. Freeman, Damian G. Weaver, Hema P. Narra, Richard W. Scott and Gill Diamond

J. Fungi 2020, 6(4), 197; https://doi.org/10.3390/jof6040197 - 30 Sep 2020

Cited by 1 | Viewed by 2669

Abstract

Disseminated infection by Candida species represents a common, often life-threatening condition. Increased resistance to current antifungal drugs has led to an urgent need to develop new antifungal drugs to treat this pathogen. However, in vivo screening of candidate antifungal compounds requires large numbers [...] Read more.

Disseminated infection by Candida species represents a common, often life-threatening condition. Increased resistance to current antifungal drugs has led to an urgent need to develop new antifungal drugs to treat this pathogen. However, in vivo screening of candidate antifungal compounds requires large numbers of animals and using immunosuppressive agents to allow for fungal dissemination. To increase the efficiency of screening, to use fewer mice, and to remove the need for immunosuppressive agents, which may interfere with the drug candidates, we tested the potential for a novel approach using in vivo imaging of a fluorescent strain of Candida albicans, in a mouse strain deficient in the host defense peptide, murine β-defensin 1 (mBD-1). We developed a strain of C. albicans that expresses red fluorescent protein (RFP), which exhibits similar infectivity to the non-fluorescent parent strain. When this strain was injected into immunocompetent mBD-1-deficient mice, we observed a non-lethal disseminated infection. Further, we could quantify its dissemination in real time, and observe the activity of an antifungal peptide mimetic drug by in vivo imaging. This novel method will allow for the rapid in vivo screening of antifungal drugs, using fewer mice, and increase the efficiency of testing new antifungal agents. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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10 pages, 981 KiB

Open AccessArticle

Designed Antimicrobial Peptides Against Trauma-Related Cutaneous Invasive Fungal Wound Infections

by Kathryn W. Woodburn, Jesse M. Jaynes and L. Edward Clemens

J. Fungi 2020, 6(3), 184; https://doi.org/10.3390/jof6030184 - 22 Sep 2020

Cited by 4 | Viewed by 2398

Abstract

Cutaneous invasive fungal wound infections after life-threatening dismounted complex blast injury (DCBI) and natural disasters complicate clinical care. These wounds often require aggressive repeated surgical debridement, can result in amputations and hemipelvectomies and have a 38% mortality rate. Given the substantial morbidity associated [...] Read more.

Cutaneous invasive fungal wound infections after life-threatening dismounted complex blast injury (DCBI) and natural disasters complicate clinical care. These wounds often require aggressive repeated surgical debridement, can result in amputations and hemipelvectomies and have a 38% mortality rate. Given the substantial morbidity associated with cutaneous fungal wound infections, patients at risk need immediate empiric treatment mandating the use of rapidly acting broad-spectrum antimicrobials, acting on both fungi and bacteria, that are also effective against biofilm and can be administered topically. Designed antimicrobial peptides (dAMPs) are engineered analogues of innate antimicrobial peptides which provide the first line of defense against invading pathogens. The antifungal and antibacterial effect and mammalian cytotoxicity of seven innovative dAMPs, created by iterative structural analog revisions and physicochemical and functional testing were investigated. The dAMPs possess broad-spectrum antifungal activity, in addition to being effective against Gram-negative and Gram-positive bacteria, which is crucial as many wounds are polymicrobial and require immediate empiric treatment. Three of the most potent dAMPs—RP504, RP556 and RP557—possess limited mammalian cytotoxicity following 8 h incubation. If these encouraging broad-spectrum antimicrobial and rapid acting results are translated clinically, these novel dAMPs may become a first line empiric topical treatment for traumatic wound injuries. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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14 pages, 1575 KiB

Open AccessArticle

Histidine-Rich Defensins from the Solanaceae and Brasicaceae Are Antifungal and Metal Binding Proteins

by Mark R. Bleackley, Shaily Vasa, Peta J. Harvey, Thomas M. A. Shafee, Bomai K. Kerenga, Tatiana P. Soares da Costa, David J. Craik, Rohan G. T. Lowe and Marilyn A. Anderson

J. Fungi 2020, 6(3), 145; https://doi.org/10.3390/jof6030145 - 24 Aug 2020

Cited by 7 | Viewed by 3143

Abstract

Plant defensins are best known for their antifungal activity and contribution to the plant immune system. The defining feature of plant defensins is their three-dimensional structure known as the cysteine stabilized alpha-beta motif. This protein fold is remarkably tolerant to sequence variation with [...] Read more.

Plant defensins are best known for their antifungal activity and contribution to the plant immune system. The defining feature of plant defensins is their three-dimensional structure known as the cysteine stabilized alpha-beta motif. This protein fold is remarkably tolerant to sequence variation with only the eight cysteines that contribute to the stabilizing disulfide bonds absolutely conserved across the family. Mature defensins are typically 46–50 amino acids in length and are enriched in lysine and/or arginine residues. Examination of a database of approximately 1200 defensin sequences revealed a subset of defensin sequences that were extended in length and were enriched in histidine residues leading to their classification as histidine-rich defensins (HRDs). Using these initial HRD sequences as a query, a search of the available sequence databases identified over 750 HRDs in solanaceous plants and 20 in brassicas. Histidine residues are known to contribute to metal binding functions in proteins leading to the hypothesis that HRDs would have metal binding properties. A selection of the HRD sequences were recombinantly expressed and purified and their antifungal and metal binding activity was characterized. Of the four HRDs that were successfully expressed all displayed some level of metal binding and two of four had antifungal activity. Structural characterization of the other HRDs identified a novel pattern of disulfide linkages in one of the HRDs that is predicted to also occur in HRDs with similar cysteine spacing. Metal binding by HRDs represents a specialization of the plant defensin fold outside of antifungal activity. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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21 pages, 4618 KiB

Open AccessArticle

The Penicillium chrysogenum Q176 Antimicrobial Protein PAFC Effectively Inhibits the Growth of the Opportunistic Human Pathogen Candida albicans

by Jeanett Holzknecht, Alexander Kühbacher, Csaba Papp, Attila Farkas, Györgyi Váradi, Jose F. Marcos, Paloma Manzanares, Gábor K. Tóth, László Galgóczy and Florentine Marx

J. Fungi 2020, 6(3), 141; https://doi.org/10.3390/jof6030141 - 19 Aug 2020

Cited by 19 | Viewed by 3512

Abstract

Small, cysteine-rich and cationic antimicrobial proteins (AMPs) from filamentous ascomycetes promise treatment alternatives to licensed antifungal drugs. In this study, we characterized the Penicillium chrysogenum Q176 antifungal protein C (PAFC), which is phylogenetically distinct to the other two Penicillium antifungal proteins, PAF and [...] Read more.

Small, cysteine-rich and cationic antimicrobial proteins (AMPs) from filamentous ascomycetes promise treatment alternatives to licensed antifungal drugs. In this study, we characterized the Penicillium chrysogenum Q176 antifungal protein C (PAFC), which is phylogenetically distinct to the other two Penicillium antifungal proteins, PAF and PAFB, that are expressed by this biotechnologically important ascomycete. PAFC is secreted into the culture broth and is co-expressed with PAF and PAFB in the exudates of surface cultures. This observation is in line with the suggested role of AMPs in the adaptive response of the host to endogenous and/or environmental stimuli. The in silico structural model predicted five β-strands stabilized by four intramolecular disulfide bonds in PAFC. The functional characterization of recombinant PAFC provided evidence for a promising new molecule in anti-Candida therapy. The thermotolerant PAFC killed planktonic cells and reduced the metabolic activity of sessile cells in pre-established biofilms of two Candidaalbicans strains, one of which was a fluconazole-resistant clinical isolate showing higher PAFC sensitivity than the fluconazole-sensitive strain. Candidacidal activity was linked to severe cell morphology changes, PAFC internalization, induction of intracellular reactive oxygen species and plasma membrane disintegration. The lack of hemolytic activity further corroborates the potential applicability of PAFC in clinical therapy. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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16 pages, 6236 KiB

Open AccessArticle

Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata

by Hannah L. Norris, Rohitashw Kumar, Chih Yean Ong, Ding Xu and Mira Edgerton

J. Fungi 2020, 6(3), 124; https://doi.org/10.3390/jof6030124 - 31 Jul 2020

Cited by 14 | Viewed by 3150

Abstract

Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen Candida albicans. Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn²⁺), although the function of this capability is incompletely understood. Hst [...] Read more.

Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen Candida albicans. Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn²⁺), although the function of this capability is incompletely understood. Hst 5 is taken up by C. albicans and acts on intracellular targets under metal-free conditions; however, Zn²⁺ is abundant in saliva and may functionally affect Hst 5. We hypothesized that Zn²⁺ binding would induce membrane-disrupting pores through dimerization. Through the use of Hst 5 and two derivatives, P113 (AA 4-15 of Hst 5) and Hst 5ΔMB (AA 1-3 and 15-19 mutated to Glu), we determined that Zn²⁺ significantly increases killing activity of Hst 5 and P113 for both C. albicans and Candida glabrata. Cell association assays determined that Zn²⁺ did not impact initial surface binding by the peptides, but Zn²⁺ did decrease cell association due to active peptide uptake. ATP efflux assays with Zn²⁺ suggested rapid membrane permeabilization by Hst 5 and P113 and that Zn²⁺ affinity correlates to higher membrane disruption ability. High-performance liquid chromatography (HPLC) showed that the higher relative Zn²⁺ affinity of Hst 5 likely promotes dimerization. Together, these results suggest peptide assembly into fungicidal pore structures in the presence of Zn²⁺, representing a novel mechanism of action that has exciting potential to expand the list of Hst 5-susceptible pathogens. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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Review

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18 pages, 3027 KiB

Open AccessReview

Host Defense Peptides as Templates for Antifungal Drug Development

by Virginia Basso, Dat Q. Tran, André J. Ouellette and Michael E. Selsted

J. Fungi 2020, 6(4), 241; https://doi.org/10.3390/jof6040241 - 23 Oct 2020

Cited by 13 | Viewed by 2615

Abstract

Current treatment for invasive fungal diseases is limited to three classes of antifungal drugs: azoles, polyenes, and echinocandins. The most recently introduced antifungal class, the echinocandins, was first approved nearly 30 years ago. The limited antifungal drug portfolio is rapidly losing its clinical [...] Read more.

Current treatment for invasive fungal diseases is limited to three classes of antifungal drugs: azoles, polyenes, and echinocandins. The most recently introduced antifungal class, the echinocandins, was first approved nearly 30 years ago. The limited antifungal drug portfolio is rapidly losing its clinical utility due to the inexorable rise in the incidence of invasive fungal infections and the emergence of multidrug resistant (MDR) fungal pathogens. New antifungal therapeutic agents and novel approaches are desperately needed. Here, we detail attempts to exploit the antifungal and immunoregulatory properties of host defense peptides (HDPs) in the design and evaluation of new antifungal therapeutics and discuss historical limitations and recent advances in this quest. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

17 pages, 289 KiB

Open AccessReview

Molecular and Biological Properties of Snakins: The Foremost Cysteine-Rich Plant Host Defense Peptides

by Tao Su, Mei Han, Dan Cao and Mingyue Xu

J. Fungi 2020, 6(4), 220; https://doi.org/10.3390/jof6040220 - 12 Oct 2020

Cited by 33 | Viewed by 2903

Abstract

Plant host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are regarded as one of the most prevalent barriers elaborated by plants to combat various infective agents. Among the multiple classes of HDPs, the Snakin class attracts special concern, as they carry [...] Read more.

Plant host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are regarded as one of the most prevalent barriers elaborated by plants to combat various infective agents. Among the multiple classes of HDPs, the Snakin class attracts special concern, as they carry 12 cysteine residues, being the foremost cysteine-rich peptides of the plant HDPs. Also, their cysteines are present at very highly conserved positions and arranged in an extremely similar way among different members. Like other plant HDPs, Snakins have been shown to exhibit strong antifungal and antibacterial activity against a wide range of plant pathogens. Moreover, they display diversified biological activities in many aspects of plant growth and the development process. This review is devoted to present the general characters of the Snakin class of plant HDPs, as well as the individual features of different Snakin family members. Specifically, the sequence properties, spatial structures, distributions, expression patterns and biological activities of Snakins are described. In addition, further detailed classification of the Snakin family members, along with their possible mode of action and potential applications in the field of agronomy and pathology are discussed. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

11 pages, 2588 KiB

Open AccessReview

Echinocandins as Biotechnological Tools for Treating Candida auris Infections

by Elizabete de Souza Cândido, Flávia Affonseca, Marlon Henrique Cardoso and Octavio Luiz Franco

J. Fungi 2020, 6(3), 185; https://doi.org/10.3390/jof6030185 - 22 Sep 2020

Cited by 12 | Viewed by 5885

Abstract

Candida auris has been reported in the past few years as an invasive fungal pathogen of high interest. Its recent emergence in healthcare-associated infections triggered the efforts of researchers worldwide, seeking additional alternatives to the use of traditional antifungals such as azoles. Lipopeptides, [...] Read more.

Candida auris has been reported in the past few years as an invasive fungal pathogen of high interest. Its recent emergence in healthcare-associated infections triggered the efforts of researchers worldwide, seeking additional alternatives to the use of traditional antifungals such as azoles. Lipopeptides, specially the echinocandins, have been reported as an effective approach to control pathogenic fungi. However, despite its efficiency against C. auris, some isolates presented echinocandin resistance. Thus, therapies focused on echinocandins’ synergism with other antifungal drugs were widely explored, representing a novel possibility for the treatment of C. auris infections. Full article

(This article belongs to the Special Issue Antifungal Peptides 2020)

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