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| Author(s): |
Thayná Lopes Barreto
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2020-10-16 |
| Examining board members: |
Kelly Ishida;
Wagner Luiz Batista;
Lucas Xavier Bonfietti;
Carlos Pelleschi Taborda
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| Advisor: | Kelly Ishida |
| Abstract | |
Invasive fungal infections are considered a major health problem because they affect mainly immunocompromised patients and have a very limited spectrum of treatment. Thus, the repositioning strategy becomes relevant and miltefosine (MFS) is purposed as a potential antifungal alternative because presents broad spectrum of action fungicide, but the high toxicity may difficult the use in clinical mycology. The use of nanostructured systems for controlled and sustained release is a way to reduce toxicity and maintain antifungal activity and miltefosine encapsulated in alginate nanoparticles (MFS-AN) is a promising strategy in the therapy of invasive fungal infections. Therefore, this work aimed to evaluate the activity of free MFS and MFS-AN on Aspergillus fumigatus (n=10), Aspergillus flavus (n=9) and Candida auris (n=2) in experimental models in vitro and in vivo using larval model of Galleria mellonella. The isolates of A. fumigatus tested were considered sensitive to standard antifungals (amphotericin B - AMB and voriconazole - VRC) while the strains of A. flavus showed a more tolerant profile. We used two isolates of C. auris: CBS 10913 was sensitive to all conventional antifungals and CBS 12766 was resistant to fluconazole. Free MFS inhibited the fungal growth in concentrations from 0.5 to 16 μg/mL; it was fungicidal for most strains of A. fumigatus and C. auris (1 to 32 μg/mL), and fungistatic for A. flavus. MFS-NA inhibited the growth of A. fumigatus, A. flavus and C. auris CBS 10913 at 18.7-600 μg/mL, while C. auris CBS 12766 was the most tolerant (Minimum Inhibitory Concentration MIC > 600 μg/mL). The synergistic effect of MFS with VRC was identified for the isolate 1220 of A. fumigatus, with a reduction of MIC by 8 times for both drugs in combination. In the G. mellonella model, MFS (20 and 40 mg/kg) and MFS-NA (100 mg/kg) reduced the mortality rate and increased the health index of larvae infected with A. fumigatus, also reducing the fungal dissemination through the larval tissue with increase of the number of granulomas of the infection control. The combination of MFS + VRC reduced the fungal burden and showed to be better than treatment with VRC alone. For infection with A. flavus it was observed that when combined MFS-NA + VRC there was an increase of larvae survival, besides the reduction of fungal burden in comparison with VRC, indicating that the treatments in combination were better than when used alone. The survival profile in G. mellonella model of the strain considered to be more virulent (CBS 12766) remained the same with the treatments, nevertheless decreased tissue dissemination was observed mainly in the groups treated with MFS (40 mg/kg) and MFS-AN. In contrast, free MFS and MFS-AN were effective against infection with C. auris CBS 10913 leading to increase of larval survival and reduction of fungal burden. Free MFS and MFS-AN presents relevant potential for antifungal therapy of aspergillosis and invasive candidiasis, and in combination with VRC may be a strategy for improving pharmacological performance in therapy against several invasive fungal infections. (AU) | |
| FAPESP's process: | 18/03708-8 - Antifungal efficacy of miltefosine in alginate nanocarrier in the treatment of aspergillosis |
| Grantee: | Thayná Lopes Barreto |
| Support Opportunities: | Scholarships in Brazil - Master |