Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis
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Radaković, NatašaNikolić, Andrea
Terzić-Jovanović, Nataša
Stojković, Pavle
Stanković, Nada
Solaja, Bogdan
Opsenica, Igor
Pavić, Aleksandar
Article (Published version)
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Candida albicans remains the main causal agent of candidiasis, the most common fungal infection with disturbingly high mortality rates worldwide. The limited diversity and efficacy of clinical antifungal drugs, exacerbated by emerging drug resistance, have resulted in the failure of current antifungal therapies. This imposes an urgent demand for the development of innovative strategies for effective eradication of candidal infections. While the existing clinical drugs display fungicidal or fungistatic activity, the strategy specifically targeting C. albicans filamentation, as the most important virulence trait, represents an attractive approach for overcoming the drawbacks related to clinical antifungals. The results acquired in this study revealed the significant potential of 5-aminotetrazoles as a new class of effective and safe anti-virulence agents. Moreover, these novel agents were active when applied both alone and in combination with clinically approved polyenes. Complete preven...tion of C. albicans morphogenetic yeast-to-hyphae transition was achieved at doses as low as 1.3 mM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio-or hepatotoxicity was observed at doses as high as 200 mM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug.
Keywords:
Zebrafish-C, albicans infection model / Inhibition of filamentation / Combination therapy / Anti-virulence activity / 5-AminotetrazolesSource:
European Journal of Medicinal Chemistry, 2022, 230Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
- Serbian Academy of Sciences and Arts [F80]
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200042 (University of Belgrade, Institute of Molecular Genetics and Genetic Engineering) (RS-MESTD-inst-2020-200042)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200168 (University of Belgrade, Faculty of Chemistry) (RS-MESTD-inst-2020-200168)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-MESTD-inst-2020-200026)
DOI: 10.1016/j.ejmech.2022.114137
ISSN: 0223-5234
PubMed: 35077918
WoS: 000812346100009
Scopus: 2-s2.0-85123253352
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Radaković, Nataša AU - Nikolić, Andrea AU - Terzić-Jovanović, Nataša AU - Stojković, Pavle AU - Stanković, Nada AU - Solaja, Bogdan AU - Opsenica, Igor AU - Pavić, Aleksandar PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1593 AB - Candida albicans remains the main causal agent of candidiasis, the most common fungal infection with disturbingly high mortality rates worldwide. The limited diversity and efficacy of clinical antifungal drugs, exacerbated by emerging drug resistance, have resulted in the failure of current antifungal therapies. This imposes an urgent demand for the development of innovative strategies for effective eradication of candidal infections. While the existing clinical drugs display fungicidal or fungistatic activity, the strategy specifically targeting C. albicans filamentation, as the most important virulence trait, represents an attractive approach for overcoming the drawbacks related to clinical antifungals. The results acquired in this study revealed the significant potential of 5-aminotetrazoles as a new class of effective and safe anti-virulence agents. Moreover, these novel agents were active when applied both alone and in combination with clinically approved polyenes. Complete prevention of C. albicans morphogenetic yeast-to-hyphae transition was achieved at doses as low as 1.3 mM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio-or hepatotoxicity was observed at doses as high as 200 mM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug. PB - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux T2 - European Journal of Medicinal Chemistry T1 - Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis VL - 230 DO - 10.1016/j.ejmech.2022.114137 ER -
@article{ author = "Radaković, Nataša and Nikolić, Andrea and Terzić-Jovanović, Nataša and Stojković, Pavle and Stanković, Nada and Solaja, Bogdan and Opsenica, Igor and Pavić, Aleksandar", year = "2022", abstract = "Candida albicans remains the main causal agent of candidiasis, the most common fungal infection with disturbingly high mortality rates worldwide. The limited diversity and efficacy of clinical antifungal drugs, exacerbated by emerging drug resistance, have resulted in the failure of current antifungal therapies. This imposes an urgent demand for the development of innovative strategies for effective eradication of candidal infections. While the existing clinical drugs display fungicidal or fungistatic activity, the strategy specifically targeting C. albicans filamentation, as the most important virulence trait, represents an attractive approach for overcoming the drawbacks related to clinical antifungals. The results acquired in this study revealed the significant potential of 5-aminotetrazoles as a new class of effective and safe anti-virulence agents. Moreover, these novel agents were active when applied both alone and in combination with clinically approved polyenes. Complete prevention of C. albicans morphogenetic yeast-to-hyphae transition was achieved at doses as low as 1.3 mM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio-or hepatotoxicity was observed at doses as high as 200 mM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug.", publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux", journal = "European Journal of Medicinal Chemistry", title = "Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis", volume = "230", doi = "10.1016/j.ejmech.2022.114137" }
Radaković, N., Nikolić, A., Terzić-Jovanović, N., Stojković, P., Stanković, N., Solaja, B., Opsenica, I.,& Pavić, A.. (2022). Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis. in European Journal of Medicinal Chemistry Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 230. https://doi.org/10.1016/j.ejmech.2022.114137
Radaković N, Nikolić A, Terzić-Jovanović N, Stojković P, Stanković N, Solaja B, Opsenica I, Pavić A. Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis. in European Journal of Medicinal Chemistry. 2022;230. doi:10.1016/j.ejmech.2022.114137 .
Radaković, Nataša, Nikolić, Andrea, Terzić-Jovanović, Nataša, Stojković, Pavle, Stanković, Nada, Solaja, Bogdan, Opsenica, Igor, Pavić, Aleksandar, "Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis" in European Journal of Medicinal Chemistry, 230 (2022), https://doi.org/10.1016/j.ejmech.2022.114137 . .