| Congresso Brasileiro de Microbiologia 2023 | Resumo: 412-1 | ||||
Resumo:Sporotrichosis is the most prevalent subcutaneous mycosis in Latin America, and considered hyperendemics in Brazil. In the last three years there has been increasing reports of South American zoonotic-transmitted cases and, this year, the first three cases of sporotrichosis by S. brasiliensis outside this continent were described (United Kingdom). In fact, this is considered the most virulent species and several reports suggest signs of reduced sensitivity or resistance to itraconazole, the drug of choice for this mycosis treatment. Effective domestic feline treatment is the key to sporotrichosis prevention and controlling but difficulties like hepatotoxic potential, exclusive oral administration and high cost has emphasized the pressing need for new therapeutic alternatives. The 1,10-phenanthroline-5,6-dione is a phenanthrene-based compound, coupled or not to transition metal ions (Cu+2+) that previously demonstrated antifungal activities against both yeast and filamentous fungi. Therefore, this study aimed at investigating the in vitro, in vivo and in silico antifungal properties of 1,10-phenanthroline-5,6-dione against S. brasiliensis. Six isolates were obtained from cats with sporotrichosis, all from the hyperendemic Brazilian region. Half of the animals were responsive (WT) while the others were nonresponsive (NWT) to itraconazole treatment. The minimum inhibitory concentrations (MICs) of the phendione and its chelates (Cu+2, Ag+), were determined by using the broth microdilution method (M27-A3 and M38-A2). Galleria mellonella survival curves were performed as the experimental in vivo testing. In silico predictions on the pharmacological and toxicity parameters were obtained by the pkCSM, OSIRIS and SwissADME softwares. Low MICs and MFCs were verified for all three drug candidates against conidia and yeasts of WT and NWT clinical isolates ranging from 0,156 to >20 µM. The most promissing compound was [Ag(phendione)2]+, providing MIC values equal to 0.3 µM for yeasts cells and 2.5 µM for conidia. The results revealed that AgNO3 showed a good inhibitory activity against yeasts cells and conidia, having MIC values of 2.5 and 5.0 µM, respectively; while CuSO4 and Cu(ClO4)2•6H2O did not disturb fungal growth. A fungicidal profile was determined since the MFC of the three tested new chemical compounds were equal to or double the determined MICs for all clinical isolates and for the ATCC G. mellonella larvae once treated with phenanthroline chelates presented an important increase in survival percentage (30-70%). A good predictive pharmacological profile was detected for all compounds with low toxicity, similar to itraconazole. 1,10-phenanthroline-5,6-dione and its chelates were proven to act as antimicrobials against yeast fungal pathogens such as Candida haemulonii, Candida albicans and also the filamentous species Phialophora verrucosa. The in vitro, in vivo and in silico unprecedented results for a dimorphic fungus point to a promising antifungal profile for the three chelates, including inhibitory and fungicidal profiles against itraconazole-resistant S. brasilensis from the Brazilian hyperendemics. Data obtained in the present investigation can contribute to the future control and prevention of sporotrichosis by S. brasiliensis, the most prevalent species of the Brazilian hyperendemics. Palavras-chave: Felis catus, Galleria mellonella, Sporotrichosis, Treatment, Zoonosis Agência de fomento:National Council for Scientific and Technological Development (PIBIC-CNPq-UFF, Brazil); Research Support Foundation in the State of Rio de Janeiro, Brazil (FAPERJ E-26/211.502/2021), Higher Education Personnel Improvement Coordination, Brazil (CAPES) | |||||