The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans

Li, Liping; Zhang, Teng; Xu, Jianrong; Wu, Jing; Wang, Yida; Qiu, Xi-Ran; Zhang, Yu; Hou, Wei-Tong; Yan, Lan; An, Mao‐Mao; Jiang, Yuanying

doi:10.3389/fmicb.2019.02071

Cited by 25 publications

(31 citation statements)

References 48 publications

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“…Locating and gathering several enzymes involved in basic cell metabolism, including the glycolysis pathway or gluconeogenesis, at the cell surface may also contribute to an increase in the pathogenic potential of microorganisms, especially those forming organized communities, i.e., biofilms, at the site of infection. Several previous reports have indicated that numerous moonlighting proteins are present at the cell surface of fungal cells forming mono- or mixed-species biofilm, or are embedded in the biofilm matrix, a location that can be achieved, for example, by their transportation inside the EVs which enables them to play a protective role under stress conditions at the cell wall or in matrix remodeling [ 28 , 55 , 111 , 119 , 156 , 157 ].…”

Section: Confirmed Roles In Candidal Virulence and Pathogenicitymentioning

confidence: 99%

Moonlighting Proteins at the Candidal Cell Surface

et al. 2020

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The cell wall in Candida albicans is not only a tight protective envelope but also a point of contact with the human host that provides a dynamic response to the constantly changing environment in infection niches. Particularly important roles are attributed to proteins exposed at the fungal cell surface. These include proteins that are stably and covalently bound to the cell wall or cell membrane and those that are more loosely attached. Interestingly in this regard, numerous loosely attached proteins belong to the class of “moonlighting proteins” that are originally intracellular and that perform essentially different functions in addition to their primary housekeeping roles. These proteins also demonstrate unpredicted interactions with non-canonical partners at an a priori unexpected extracellular location, achieved via non-classical secretion routes. Acting both individually and collectively, the moonlighting proteins contribute to candidal virulence and pathogenicity through their involvement in mechanisms critical for successful host colonization and infection, such as the adhesion to host cells, interactions with plasma homeostatic proteolytic cascades, responses to stress conditions and molecular mimicry. The documented knowledge of the roles of these proteins in C. albicans pathogenicity has utility for assisting the design of new therapeutic, diagnostic and preventive strategies against candidiasis.

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Section: Confirmed Roles In Candidal Virulence and Pathogenicitymentioning

confidence: 99%

Moonlighting Proteins at the Candidal Cell Surface

et al. 2020

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“…C. albicans, however, has developed a high drug resistance to fluconazole through multiple underlying mechanisms [47,48]. One alternative strategy for treating candidiasis is to treat with compounds that are synergistically active with azoles in combination with azole treatment [49][50][51]. In order to investigate whether SU is synergistically active against C. albicans in combination with azoles, we tested a combination of this lipopeptide with the triazole compounds, fluconazole and itraconazole.…”

Section: Surfactin Acts In Synergy With Azole Compounds To Inhibit Cmentioning

confidence: 99%

Fluconazole and Lipopeptide Surfactin Interplay During Candida albicans Plasma Membrane and Cell Wall Remodeling Increases Fungal Immune System Exposure

et al. 2020

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Recognizing the β-glucan component of the Candida albicans cell wall is a necessary step involved in host immune system recognition. Compounds that result in exposed β-glucan recognizable to the immune system could be valuable antifungal drugs. Antifungal development is especially important because fungi are becoming increasingly drug resistant. This study demonstrates that lipopeptide, surfactin, unmasks β-glucan when the C. albicans cells lack ergosterol. This observation also holds when ergosterol is depleted by fluconazole. Surfactin does not enhance the effects of local chitin accumulation in the presence of fluconazole. Expression of the CHS3 gene, encoding a gene product resulting in 80% of cellular chitin, is downregulated. C. albicans exposure to fluconazole changes the composition and structure of the fungal plasma membrane. At the same time, the fungal cell wall is altered and remodeled in a way that makes the fungi susceptible to surfactin. In silico studies show that surfactin can form a complex with β-glucan. Surfactin forms a less stable complex with chitin, which in combination with lowering chitin synthesis, could be a second anti-fungal mechanism of action of this lipopeptide.

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“…Candida albicans SC5314, Cryptococcus neoformans ATCC32609 and ATCC 34877 are the standard strains used in many fungal studies. Other strains mentioned above are clinical isolates, which were obtained from Changhai Hospital, Shanghai and used in our previous studies (Li et al, 2017(Li et al, , 2019. The fungal strains are usually cultured in YPD liquid medium.…”

Section: Strains Mediums and Agentsmentioning

confidence: 99%

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

et al. 2020

Front. Cell. Infect. Microbiol.

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A gradual rise in immunocompromised patients over past years has led to the increasing incidence of invasive fungal infections. Development of effective fungicides can not only provide new means for clinical treatment, but also reduce the occurrence of fungal resistance. We identified a new antifungal agent (4-phenyl-1, 3-thiazol-2-yl), hydrazine (numbered as 31C) which showed high-efficiency, broad-spectrum and specific activities. The minimum inhibitory concentration of 31C against pathogenic fungi was between 0.0625-4 µg/ml in vitro, while 31C had no obvious cytotoxicity to human umbilical vein endothelial cells with the concentration of 4 µg/ml. In addition, 31C of 0.5 µg/ml could exhibit significant fungicidal activity and inhibit the biofilm formation of C. albicans. In vivo fungal infection model showed that 31C of 10 mg/kg significantly increased the survival rate of Galleria mellonella. Further study revealed that 31C-treatment increased the reactive oxygen species (ROS) in C. albicans and elevated the expression of some genes related to anti-oxidative stress response, including CAP1, CTA1, TRR1, and SODs. Consistently, 31C-induced high levels of intracellular ROS resulted in considerable DNA damage, which played a critical role in antifungal-induced cellular death. The addition of ROS scavengers, such as glutathione (GSH), N-Acetyl-L-cysteine (NAC) or oligomeric proanthocyanidins (OPC), dramatically reduced the antifungal activities of 31C and rescued the 31C-induced filamentation defect. Collectively, these results showed that 31C exhibited strong antifungal activity and induced obvious oxidative damage, which indicated that compounds with a structure similar to 31C may provide new sight for antifungal drug development.

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The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans

Cited by 25 publications

References 48 publications

Moonlighting Proteins at the Candidal Cell Surface

Moonlighting Proteins at the Candidal Cell Surface

Fluconazole and Lipopeptide Surfactin Interplay During Candida albicans Plasma Membrane and Cell Wall Remodeling Increases Fungal Immune System Exposure

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

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