Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review

Qin, Yanghua; Wang, Jinxin; Lv, Quanzhen; Han, Bing

doi:10.1128/aac.00003-23

Cited by 6 publications

(5 citation statements)

References 84 publications

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“…Mitochondria is an essential target for the cell. Thus, compounds that act exclusively or partially on this target may show antifungal activity and be useful in the treatment of fungal infections [12].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Mitochondria are responsible for yeast metabolism and their dysfunction, caused by drugs, influences viability, proliferation, virulence and drug resistance [9][10][11][12]. Thus, mitochondria are currently considered a target for the development of antifungal drugs [9,11,12]. The effect of antifungal drugs on mitochondria may include increased permeability, adenosine triphosphate (ATP) alterations, increased reactive oxygen species (ROS) production and induction of apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, mitochondria are currently considered a target for the development of antifungal drugs [9,11,12]. The effect of antifungal drugs on mitochondria may include increased permeability, adenosine triphosphate (ATP) alterations, increased reactive oxygen species (ROS) production and induction of apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

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Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei

Costa,

Lopes,

Morais

et al. 2024

IJMS

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Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 µg/mL for C. krusei and of 128 µg/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 mg/mL and a HC10 value against human red blood cells of 0.8 mg/mL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei

Costa,

Lopes,

Morais

et al. 2024

IJMS

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“…In addition to destructing the cell membrane, mitochondrial dysfunction plays an important role in the potential mechanisms of antifungal drugs [48]. Xin et al reported that antofine against P. digitatum is related to the cell membrane integrity and energy metabolism by affecting intracellular ATP content [49].…”

Section: Discussionmentioning

confidence: 99%

New Polyene Macrolide Compounds from Mangrove-Derived Strain Streptomyces hiroshimensis GXIMD 06359: Isolation, Antifungal Activity, and Mechanism against Talaromyces marneffei

Wang,

Yin,

Bai

et al. 2024

Marine Drugs

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Mangrove-derived actinomycetes represent a rich source of novel bioactive natural products in drug discovery. In this study, four new polyene macrolide antibiotics antifungalmycin B-E (1–4), along with seven known analogs (5–11), were isolated from the fermentation broth of the mangrove strain Streptomyces hiroshimensis GXIMD 06359. All compounds from this strain were purified using semi-preparative HPLC and Sephadex LH-20 gel filtration while following an antifungal activity-guided fractionation. Their structures were elucidated through spectroscopic techniques including UV, HR-ESI-MS, and NMR. These compounds exhibited broad-spectrum antifungal activity against Talaromyces marneffei with minimum inhibitory concentration (MIC) values being in the range of 2–128 μg/mL except compound 2. This is the first report of polyene derivatives produced by S. hiroshimensis as bioactive compounds against T. marneffei. In vitro studies showed that compound 1 exerted a significantly stronger antifungal activity against T. marneffei than other new compounds, and the antifungal mechanism of compound 1 may be related to the disrupted cell membrane, which causes mitochondrial dysfunction, resulting in leakage of intracellular biological components, and subsequently, cell death. Taken together, this study provides a basis for compound 1 preventing and controlling talaromycosis.

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Targeting New Functions and Applications of Bacterial Two‐Component Systems

Ji,

Li,

Liu

et al. 2024

ChemBioChem

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Two‐component signal transduction systems (TCSs) are regulatory systems widely distributed in eubacteria, archaea, and a few eukaryotic organisms, but not in mammalian cells. A typical TCS consists of a histidine kinase and a response regulator protein. Functional and mechanistic studies on different TCSs have greatly advanced the understanding of cellular phosphotransfer signal transduction mechanisms. In this concept paper, we focus on the His‐Asp phosphotransfer mechanism, the ATP synthesis function, antimicrobial drug design, cellular biosensors design, and protein allostery mechanisms based on recent TCS investigations to inspire new applications and future research perspectives.

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Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review

Abstract: Fungal infections, which commonly occur in immunocompromised patients, can cause high morbidity and mortality. Antifungal agents act by disrupting the cell membrane, inhibiting nucleic acid synthesis and function, or inhibiting β-1,3-glucan synthase.

Cited by 6 publications

References 84 publications

Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei

Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei

New Polyene Macrolide Compounds from Mangrove-Derived Strain Streptomyces hiroshimensis GXIMD 06359: Isolation, Antifungal Activity, and Mechanism against Talaromyces marneffei

Targeting New Functions and Applications of Bacterial Two‐Component Systems

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