Ketoconazole/calix[n]arenes-based compounds improve the antifungal activity against azole-resistant Candida isolates

Cristina de Castro Spadari; Thayná Lopes Barreto; Vagner Tebaldi de Queiroz; Walysson Ferreira de Paiva; Sergio Antonio Fernandes; Ângelo de Fátima; Kelly Ishida

doi:10.1016/j.mycmed.2022.101254

Ketoconazole/calix[n]arenes-based compounds improve the antifungal activity against azole-resistant Candida isolates

J Mycol Med. 2022 May;32(2):101254. doi: 10.1016/j.mycmed.2022.101254. Epub 2022 Feb 6.

Authors

Cristina de Castro Spadari¹, Thayná Lopes Barreto¹, Vagner Tebaldi de Queiroz², Walysson Ferreira de Paiva³, Sergio Antonio Fernandes³, Ângelo de Fátima⁴, Kelly Ishida⁵

Affiliations

¹ Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
² Department of Chemistry and Physics, Exact, Natural and Health Sciences Center, Federal University of Espírito Santo, Brazil.
³ Department of Chemistry, CCE, Federal University of Viçosa, Minas Gerais, Brazil.
⁴ Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil.
⁵ Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: ishidakelly@usp.br.

PMID: 35168160
DOI: 10.1016/j.mycmed.2022.101254

Abstract

Ketoconazole (KTZ) is an antifungal agent; however, its bioavailability and therapeutic efficacy are reduced by the low aqueous solubility of the drug. Aiming at providing to improve the biopharmaceutical properties of KTZ, we studied the water-soluble different calix[n]arenes as carrier systems for KTZ. All calix[n]arene-KTZ tested showed in vitro antifungal activity superior or similar to free KTZ against Candida spp. The CX6Na/KTZ obtained by physical mixture and freeze-drying methods were the most active, decreasing KTZ concentrations required for growth inhibition against azole-resistant isolates (e.g., C. auris). Moreover, CX6Na/KTZ showed no toxic effect on Galleria mellonella larvae and the treatment of infected larvae with C. albicans and C. auris was effective at a lower dose compared with free KTZ. Thus, CX6Na/KTZ may have a potential approach to treat mycosis, especially by improvement of KTZ inhibitory activity against azole-resistant Candida.

Keywords: Candida auris; Drug carrier; Galleria mellonella; Imidazole; in vivo studies.

MeSH terms

Antifungal Agents* / pharmacology
Azoles / pharmacology
Candida
Candida albicans
Ketoconazole* / pharmacology
Microbial Sensitivity Tests

Substances

Antifungal Agents
Azoles
Ketoconazole