The Antifungal Occidiofungin Triggers an Apoptotic Mechanism of Cell Death in Yeast

Emrick, Dayna; Ravichandran, Akshaya; Gosai, Jiten; Lu, Shi‐En; Gordon, Donna M.; Smith, Linda L.

doi:10.1021/np300678e

Cited by 35 publications

(48 citation statements)

References 63 publications

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“…The same mechanism has already been described for AMB (Phillips et al, 2003) and for other antifungals (Wu et al, 2010; Aerts et al, 2011; Emrick et al, 2013). …”

Section: Discussionsupporting

confidence: 63%

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

et al. 2017

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The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans, however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans. HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn2+, Zn2+, and Fe2+. The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans. Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections.

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“…The same mechanism has already been described for AMB (Phillips et al, 2003) and for other antifungals (Wu et al, 2010; Aerts et al, 2011; Emrick et al, 2013). …”

Section: Discussionsupporting

confidence: 63%

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

et al. 2017

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“…(Color figure online) World J Microbiol Biotechnol divided into 3 types according to their mechanism against pathogenic fungi. The first type includes polyenes, azoles and allylamines that primarily target ergosterol biosynthesis or bind to ergosterol to disrupt the fungal membrane (Emrick et al 2013). Ergosterol is important for maintaining proper cell permeability and fluidity.…”

Section: Discussionmentioning

confidence: 99%

Antifungal activity of Brevibacillus laterosporus JX-5 and characterization of its antifungal components

Jiang

Wang

Xiao

et al. 2015

World J Microbiol Biotechnol

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The establishment of safe and effective methods for controlling fungal disease is an urgent issue in agriculture and forestry. Microbiological control of plant disease is expected to achieve better results than use of chemically derived fungicides. This study aimed to establish Brevibacillus laterosporus JX-5 as a potential microbiological control agent of poplar canker. The bacterium was isolated from the poplar rhizosphere and demonstrated significant growth inhibition of several pathogenic fungi in vitro. The antifungal components of Br. laterosporus JX-5 were isolated and identified. The fermentation broth of Br. laterosporus JX-5 and its main antifungal component, designated as component B, reduced Botryosphaeria dothidea associated canker of the excised poplar branch by 70 and 90%, respectively. Component B is considerably heat-stable, adaptable to a broad pH range, and UV-resistant. It could inhibit Bo. dothidea by permeating the fungal membrane, fracturing the nuclei, damaging the cell wall, and eventually killing the pathogenic fungus. The antifungal activity exhibited by Br. laterosporus JX-5 and its bioactive metabolic products indicate its feasibility as a potential biocontrol agent for plant diseases.

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“…Deletion of the yca1 gene provides a 2-fold increase in resistance. All of the autophagy mutants screened had no difference in sensitivity compared to the wild-type control [2]. Results from previous experiments demonstrate that yeast cells were dying by an apoptotic mechanism of action.…”

Section: Discussionmentioning

confidence: 85%

“…Viability, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), reactive oxygen species (ROS) detection, membrane and cell wall stability, and membrane mimetic assays were used in a previous study to characterize the effect of occidiofungin on yeast cells [2]. Confocal and electron microscopy experiments were used to visualize morphological changes within treated cells.…”

Section: Discussionmentioning

confidence: 99%

“…Potent fungicidal activity was observed against Candida albicans following a short term exposure to occidiofungin for only one hour, suggesting that occidiofungin has a strong interaction with a cellular target [1]. Furthermore, the mechanism of cell death in yeast has been determined to be apoptotic [2]. These results indicate that occidiofungin is distinctive from the four existing classes of clinically used antifungal drugs and that occidiofungin's potential as a therapeutic agent warrants further investigation.…”

Section: Introductionmentioning

confidence: 87%

See 1 more Smart Citation

Toxicological Evaluation of Occidiofungin against Mice and Human Cancer Cell Lines

Hing¹,

Ravichandran²,

Escano³

et al. 2014

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Occidiofungin, a glyco-lipopeptide obtained from the liquid culture of Burkholderia contaminans MS14, has been identified as a novel fungicide. The natural product was shown to have a minimal amount of toxicity in a previous mouse toxicity study following intraperitoneal and subcutaneous administration. In this study, the toxicity of occidiofungin was evaluated following a 5 mg/kg intravenous tail vein injection. In addition, the toxicity of occidiofungin was evaluated against human fibroblast and cancer cell lines. Weight loss was the most significant observation following intravenous administration of occidiofungin. Histology, hematology, and blood serum chemistry did not reveal any significant signs of toxicity. The activity observed in the in vitro cytotoxicity assay against the cancer cell lines was all below 75 nM concentration of occidiofungin. To date, the potency of occidiofungin against these cancer cell lines is greater than any activity observed against fungi. The findings in this study support the need to further evaluate occidiofungin's chemotherapeutic potential.

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The Antifungal Occidiofungin Triggers an Apoptotic Mechanism of Cell Death in Yeast

Cited by 35 publications

References 63 publications

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

Antifungal activity of Brevibacillus laterosporus JX-5 and characterization of its antifungal components

Toxicological Evaluation of Occidiofungin against Mice and Human Cancer Cell Lines

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