Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation

Liu, Ying; Chang, Wenqiang; Zhang, Ming; Li, Xiaobin; Jiao, Yang; Lou, Hongxiang

doi:10.1371/journal.pone.0128693

Cited by 59 publications

(60 citation statements)

References 37 publications

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“…33 We found that treatment of C. albicans ATCC 10231 (strain A ) with compounds 4F and 7Aa at their 1× and 2× MIC values increased intracellular ROS production in this fungal strain (Figure 2). As expected, the H 2 O 2 positive control (at 1 mM) also induced ROS production in yeast cell, whereas no ROS induction was observed with untreated yeast cells (negative control).…”

Section: Resultsmentioning

confidence: 81%

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

Shrestha

Kril

Green

et al. 2017

Bioorganic & Medicinal Chemistry

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The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicr obial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step, resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum antibacterial and antifungal activities against most of the tested strains with minimum inhibitory concentration (MIC) values ranging from <0.5->500 μM against bacteria and 1.0->31.3 μg/mL against fungi; and in most cases, they exhibited either superior or similar antimicrobial activity compared to those of the standard drugs used in the clinic. We also observed minimal emergence of drug resistance to these newly synthesized compounds by bacteria and fungi even after 15 passages, and we found weak to moderate inhibition of the human Ether-à-go-go-related gene (hERG) channel with acceptable IC50 values ranging from 1.12-3.29 μM. Overall, these studies sh ow that bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones are potentially promising scaffolds for the discovery of novel antibacterial and antifungal agents.

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Section: Resultsmentioning

confidence: 81%

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

Shrestha

Kril

Green

et al. 2017

Bioorganic & Medicinal Chemistry

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“…FLC treatment also enhanced ROS production, especially in the 5 and 50 μg/mL groups 25 . In another study, Li et al showed that treatment with 8 μg/mL of AMB significantly increased the ROS production in C. albicans 26 . According to the literatures and our experiment results, we used 25 μg/mL FLC or (and) 2 μg/mL AMB as positive controls for the antifungal mechanism research in the current study.…”

Section: Discussionmentioning

confidence: 95%

A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

Cao

et al. 2020

Sci Rep

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In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, BN-3b with antifungal activity against Candida albicans, was achieved. In this study, we found that oxidative damage induced by endogenous reactive oxygen species (ROS) plays an important role in the antifungal activity of BN-3b. Further investigation indicated that BN-3b stimulated ROS accumulation, increased malondialdehyde (MDA) levels, and decreased reduced/oxidized glutathione (GSH/GSSG) ratio. Moreover, BN-3b decreased mitochondrial membrane potential (MMP) and ATP generation. Ultrastructure analysis revealed that BN-3b severely damaged the cell membrane of C. albicans. Quantitative PCR (RT-qPCR) analysis revealed that virulence factors of C. albicans SAPs, PLB1, PLB2, HWP1, ALSs, and LIPs were all down-regulated after BN-3b exposure. We also found that BN-3b markedly inhibited the hyphal formation of C. albicans. In addition, in vivo studies revealed that BN-3b significantly prolonged survival and decreased fungal burden in mouse model of disseminated candidiasis.Candida albicans is an opportunistic fungal pathogen 1 , causing skin and mucosal infections in healthy individuals 2 . Moreover, C. albicans can cause fatal systemic disease when immune function is damaged 3 . Disseminated candidiasis caused by C. albicans is the main cause of death in immunocompromised patients 3,4 .Borrelidin (BN), an 18-membered macrolide polyketide 5 , was isolated from the fermentation broth of Streptomyces vinaceusdrappus 6 . In the process of investigating the antifungal SAR of BN and discovering antifungal leads, forty-seven borrelidin derivatives (BNs) were synthesized by our research group 5 . Among them, a BN ester analogue BN-3b was greatly promising antifungal candidate. The MIC (minimum inhibitory concentration) values of BN-3b against C. albicans and Candida parapsilosis were 50 μg/mL and 12.5 μg/mL, respectively (Table 1). In this study, we will explore the antifungal mechanism of BN-3b.Several studies have suggested that endogenous ROS mediated oxidative damage participate in the antifungal activity of amphotericin B (AMB) and fluconazole (FLC) 7-11 . These findings implied that oxidative stress involved in the antifungal mechanism of antifungal agents. ROS are the byproducts of cellular metabolism and mainly produced in the mitochondria 12 . However, overproduction of ROS resulted in damage of nucleic acids, proteins, and lipids 4 .C. albicans has developed an effective battery of virulence factors 13 that promote disease establishment and progression 14 . Among these virulence factors, lipases (LIPs), phospholipases, agglutinin-like sequences (ALSs), secreted aspartyl proteinases (SAPs), and hyphal wall protein (HWP1) are most significant in virulence [14][15][16][17] . Fungal virulence factors are potential targets for drug development 15 . In this study, we determined the expression of virulence factors (SAPs, PLB1, PLB2, HWP1, ALSs, and LIP...

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“…In order to determine if bisbenzimidazoles are capable of inducing ROS, we investigated the effect of two of our best compounds, 2 and 9 , against C. albicans ATCC 10231 (strain A ) in a dose depend manner at 1× and 2× MIC using a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) dye. 39 Generally, ROS is generated in mitochondria of eukaryotic cells as a byproduct during cellular metabolism. Cells neutralize the excess ROS production by activating their antioxidant functions.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents

Chandrika

Shrestha

Ngo

2016

Bioorganic & Medicinal Chemistry

105

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The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanism of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6–0.975 µg/mL The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested.

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Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation

Cited by 59 publications

References 37 publications

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents

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