(+)-Medioresinol leads to intracellular ROS accumulation and mitochondria-mediated apoptotic cell death in Candida albicans

Hwang, Jun Hyun; Hwang, In-sok; Liu, Qing-He; Woo, Eun‐Rhan; Lee, Dong Gun

doi:10.1016/j.biochi.2012.04.010

Cited by 81 publications

(52 citation statements)

References 45 publications

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“…The formation of reactive oxygen species (ROS) has been suggested to be one of the fungicidal mechanisms of a large number of fungicidal antibiotics [31]. In order to determine whether ROS mediated the antifungal activity of ATB, we examined the ROS levels of C. albicans cells treated with or without ATB by fluorimetric assay.…”

Section: Resultsmentioning

confidence: 99%

Alteramide B is a microtubule antagonist of inhibiting Candida albicans

Ding

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Alteramide B (ATB), isolated from Lysobacter enzymogenes C3, was a new polycyclic tetramate macrolactam (PTM). ATB exhibited potent inhibitory activity against several yeasts, particularly Candida albicans SC5314, but its antifungal mechanism is unknown. Methods The structure of ATB was established by extensive spectroscopic analyses, including high-resolution mass spectrometry, 1D- and 2D-NMR, and CD spectra. Flow cytometry, fluorescence microscope, transmission electron microscope, molecular modeling, overexpression and site-directed mutation studies were employed to delineate the anti-candida molecular mechanism of ATB. Results ATB induced apoptosis in C. albicans through inducing reactive oxygen species (ROS) production by disrupting microtubules. Molecular dynamics studies revealed the binding patterns of ATB to the β-tubulin subunit. Overexpression of the wild type and site-directed mutants of the β-tubulin gene (TUBB) changed the sensitivity of C. albicans to ATB, confirming the binding of ATB to β-tubulin, and indicating that the binding sites are L215, L217, L273, L274 and R282. In vivo, ATB significantly improved the survival of the candidiasis mice and reduced fungal burden. Conclusion The molecular mechanism underlying the ATB-induced apoptosis in C. albicans is through inhibiting tubulin polymerization that leads to cell cycle arrest at the G2/M phase. The identification of ATB and the study of its activity provide novel mechanistic insights into the mode of action of PTMs against the human pathogen. General significance This study shows that ATB is a new microtubule inhibitor and a promising anti-Candida lead compound. The results also support β-tubulin as a potential target for anti-Candida drug discovery.

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Section: Resultsmentioning

confidence: 99%

Alteramide B is a microtubule antagonist of inhibiting Candida albicans

Ding

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…These phytochemicals are essential to a plant’s reproductive system and usually prevent the entry of pathogenic microorganism which is spreading throughout the plants. Among the phytochemicals from plant, the antimicrobial property and mode of actions of certain compounds such as (+)-Medioresinol (Hwang et al, 2012) and amentoflavone (Hwang et al, 2013) have been well reported earlier. In this study, we reported the antifungal property of protolichesterinic acid from U. albopunctata and explained its mode of action against C. tropicalis for the first time.…”

Section: Discussionmentioning

confidence: 99%

An Antifungal Mechanism of Protolichesterinic Acid from the Lichen Usnea albopunctata Lies in the Accumulation of Intracellular ROS and Mitochondria-Mediated Cell Death Due to Apoptosis in Candida tropicalis

Kumar

Mohandas

2017

Front. Pharmacol.

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Candida species causes superficial and life-threatening systemic infections and are difficult to treat due to the resistance of these organism to various clinically used drugs. Protolichesterinic acid is a well-known lichen compound. Although the antibacterial activity of protolichesterinic acid has been reported earlier, the antifungal property and its mechanism of action are still largely unidentified. The goal of the present investigation is to explore the anticandidal activity and mechanism of action of protolichesterinic acid, especially against Candida tropicalis. The Minimum Inhibitory Concentration (MIC) value was established through microdilution techniques against four Candida species and out of four species tested, C. tropicalis showed a significant effect (MIC: 2 μg/ml). In the morphological interference assay, we observed the enhanced inhibition of hyphae when the cells were treated with protolichesterinic acid. Time-kill assay demonstrated that the maximum rate of killing was recorded between 2 and 6 h. C. tropicalis exposed to protolichesterinic acid exhibited an increased ROS production, which is one of the key factors of fungal death. The rise in ROS was due to the dysfunction of mitochondria caused by protolichesterinic acid. We confirmed that protolichesterinic acid-induced dysfunction of mitochondria in C. tropicalis. The damage of cell membrane due to protolichesterinic acid treatment was confirmed by the influx of propidium iodide and was further confirmed by the release of potassium ions. The treatment of protolichesterinic acid also triggered calcium ion signaling. Moreover, it commenced apoptosis which is clearly evidenced by Annexin V and propidium iodide staining. Interestingly protolichesterinic acid recorded excellent immunomodulatory property when tested against lymphocytes. Finally protolichesterinic acid showed low toxicity toward a normal human cell line Foreskin (FS) normal fibroblast. In in vivo test, protolichesterinic acid significantly enhanced the survival of C. tropicalis infected Caenorhabditis elegans. This investigation proposes that the protolichesterinic acid induces apoptosis in C. tropicalis via the enhanced accumulation of intracellular ROS and mitochondrial damage, which leads fungal cell death via apoptosis. Our work revealed a new key aspect of mechanisms of action of protolichesterinic acid in Candida species. This article is the first study on the antifungal and mechanism of action of protolichesterinic acid in Candida species.

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“…ROS accumulation and eventually apoptosis and/or necrosis in fungal pathogens has been demonstrated for several chemical compounds isolated from plants, such as shikonin from roots of Lithospermum erythrorhizon [76], medioresinol from stem bark of Sambucus williamsii [77], styraxjaponoside C from stem bark of Styrax japonica [78], amentoflavone from Selaginella tamariscina [79], dill seed essential oil (Anethum graveolens) [80,81], the polyphenol curcumin [82], plagiochin E from liverwort Marchantia polymorpha [83,84] and baicalein from Scutellaria baicaleinsis roots [85]. Moreover, the plant defensins HsAFP1 (Heuchera sanguinea), RsAFP2 (Raphinus sativus) and PvD1 (Phaseolus vulgaris), active against several yeast and fungal species were found to induce ROS accumulation in C. albicans and Fusarium oxysporum [86][87][88].…”

Section: Novel Ros-inducing Antifungal Agentsmentioning

confidence: 99%

Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms

2013

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Invasive fungal infections are associated with very high mortality rates ranging from 20-90% for opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungal resistance to antimycotic treatment can be genotypic (due to resistant strains) as well as phenotypic (due to more resistant fungal lifestyles, such as biofilms). With regard to the latter, biofilms are considered to be critical in the development of invasive fungal infections. However, there are only very few antimycotics, such as miconazole (azoles), echinocandins and liposomal formulations of amphotericin B (polyenes), which are also effective against fungal biofilms. Interestingly, these antimycotics all induce reactive oxygen species (ROS) in fungal (biofilm) cells. This review provides an overview of the different classes of antimycotics and novel antifungal compounds that induce ROS in fungal planktonic and biofilm cells. Moreover, different strategies to further enhance the antibiofilm activity of such ROS-inducing antimycotics will be discussed.

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(+)-Medioresinol leads to intracellular ROS accumulation and mitochondria-mediated apoptotic cell death in Candida albicans

Cited by 81 publications

References 45 publications

Alteramide B is a microtubule antagonist of inhibiting Candida albicans

Alteramide B is a microtubule antagonist of inhibiting Candida albicans

An Antifungal Mechanism of Protolichesterinic Acid from the Lichen Usnea albopunctata Lies in the Accumulation of Intracellular ROS and Mitochondria-Mediated Cell Death Due to Apoptosis in Candida tropicalis

Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms

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