Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis
Samo za registrovane korisnike
2022
Autori
Radaković, NatašaNikolić, Andrea

Terzić-Jovanović, Nataša

Stojković, Pavle

Stanković, Nada

Šolaja, Bogdan

Opsenica, Igor

Pavić, Aleksandar

Članak u časopisu (Objavljena verzija)

Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 μM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio- or hepatotoxicity was observed at doses as high as 200 μM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5-aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5-aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug.
Ključne reči:
5-Aminotetrazoles / Anti-virulence activity / Combination therapy / Inhibition of filamentation / Zebrafish- infection modelIzvor:
European Journal of Medicinal Chemistry, 2022, 230, 114137-Izdavač:
- Elsevier
Finansiranje / projekti:
- Ministarstvo prosvete, nauke i tehnološkog razvoja Republike Srbije, Ugovor br. 200042 (Univerzitet u Beogradu, Institut za molekularnu genetiku i genetičko inženjerstvo) (RS-200042)
- Ministarstvo prosvete, nauke i tehnološkog razvoja Republike Srbije, Ugovor br. 200168 (Univerzitet u Beogradu, Hemijski fakultet) (RS-200168)
- Ministarstvo prosvete, nauke i tehnološkog razvoja Republike Srbije, Ugovor br. 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-200026)
- Serbian Academy of Sciences and Arts (Project No. F80)
DOI: 10.1016/j.ejmech.2022.114137
ISSN: 0223-5234
WoS: 00081234610000
Scopus: 2-s2.0-85123253352
Institucija/grupa
IHTMTY - JOUR AU - Radaković, Nataša AU - Nikolić, Andrea AU - Terzić-Jovanović, Nataša AU - Stojković, Pavle AU - Stanković, Nada AU - Šolaja, Bogdan AU - Opsenica, Igor AU - Pavić, Aleksandar PY - 2022 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/5235 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 μM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio- or hepatotoxicity was observed at doses as high as 200 μM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5-aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5-aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug. PB - Elsevier 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 SP - 114137 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 Šolaja, 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 μM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio- or hepatotoxicity was observed at doses as high as 200 μM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5-aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5-aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug.", publisher = "Elsevier", 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", pages = "114137", doi = "10.1016/j.ejmech.2022.114137" }
Radaković, N., Nikolić, A., Terzić-Jovanović, N., Stojković, P., Stanković, N., Šolaja, 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., 230, 114137. https://doi.org/10.1016/j.ejmech.2022.114137
Radaković N, Nikolić A, Terzić-Jovanović N, Stojković P, Stanković N, Šolaja 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;230:114137. doi:10.1016/j.ejmech.2022.114137 .
Radaković, Nataša, Nikolić, Andrea, Terzić-Jovanović, Nataša, Stojković, Pavle, Stanković, Nada, Šolaja, 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):114137, https://doi.org/10.1016/j.ejmech.2022.114137 . .