Ketoconazole/calix[n]arenes-based compounds improve the antifungal activity against azole-resistant Candida isolates - 18/05/22

Doi : 10.1016/j.mycmed.2022.101254

Cristina de Castro Spadari ^a,^{^{#
The authors worked equally.}}, Thayná Lopes Barreto ^a,^{^{#
The authors worked equally.}}, Vagner Tebaldi de Queiroz ^b, Walysson Ferreira de Paiva ^c, Sergio Antonio Fernandes ^c, Ângelo de Fátima ^d, Kelly Ishida ^a,^⁎
^a Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
^b Department of Chemistry and Physics, Exact, Natural and Health Sciences Center, Federal University of Espírito Santo, Brazil
^c Department of Chemistry, CCE, Federal University of Viçosa, Minas Gerais, Brazil
^d Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil

^⁎Correspondence author at: Kelly Ishida, Laboratory of Antifungal Chemotherapy, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 1374 – 05508-000, ICB II, Lab 150, São Paulo, SP, Brazil.Laboratory of Antifungal Chemotherapy, Department of MicrobiologyInstitute of Biomedical Sciences, University of São PauloProf. Lineu Prestes Avenue, 1374 – 05508-000, ICB II, Lab 150São PauloSPBrazil

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.

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

Esquema

Introduction

Material and methods

Production of ketoconazole-calix[n]arene compounds

Antifungal susceptibility testing

Toxicity and antifungal efficacy in Galleria mellonella larval model

Statistical analysis

Results and discussion

Funding

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Vol 32 - N° 2

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Ketoconazole/calix[n]arenes-based compounds improve the antifungal activity against azole-resistant Candida isolates - 18/05/22

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