Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans
Abstract
:1. Introduction
2. Materials and Methods
2.1. Fungi and Growth Conditions
2.2. Test Compounds
2.3. Antifungal Susceptibility Profile of Clinically Available Antifungal Agents
2.4. Assessment of the Potential Antifungal Activity of Test Compounds
2.5. Chemical Stability of the Test Compounds
2.6. Prediction of Drug-Likeness and Pharmacokinetics of the Test Compounds
2.7. Hemolysis Assay
2.8. In Vivo Toxicity of the Test Compounds in Galleria mellonella
2.8.1. Single Treatment (Acute Toxicity)
2.8.2. Multiple Treatment (Chronic Toxicity)
2.9. Hemocyte Density Analysis
2.10. Statistical Analyses
3. Results
3.1. Susceptibility Profile of Cryptococcus Clinical Isolates to Conventional Antifungal Agents
3.2. Impact of Test Compounds on Fungal Viability
3.3. Assessment of the Stability of Antifungal Activity in the Evaluated Complexes
3.4. Prediction of Drug-Likeness and Pharmacokinetics of Test Complexes
3.5. Hemolysis Assay
3.6. In Vivo Toxicity of Test Complexes in G. mellonella
3.6.1. Acute Toxicity (Single Dose Treatment)
3.6.2. Chronic Toxicity (Multiple Dose Treatment)
3.7. Hemocyte Density Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cryptococcus Species | Isolate | MIC, [µg/mL] | ||||
---|---|---|---|---|---|---|
Amphotericin B | Caspofungin | Fluconazole | Flucytosine | Voriconazole | ||
C. neoformans | 213 | 0.03 (0.03 µM) | >8 (>7.30 µM) | 4 (13 µM) | 4 (30 µM) | 0.5 (1.4 µM) * |
223 | >16 (>17.30 µM) * | >8 (>7.30 µM) | >64 (>208 µM) * | 64 (495.76 µM) * | 16 (45.80 µM) * | |
350 | 0.03 (0.03 µM) | >8 (>7.30 µM) | 8 (26.12 µM) | 16 (123.94 µM) * | 2 (5.72 µM) * | |
C. gattii | 27 | 0.03 (0.03 µM) | >8 (>7.30 µM) | 16 (52.24 µM) | 4 (30 µM) | 4 (11.45 µM) * |
25 | 0.03 (0.03 µM) | >8 (>7.30 µM) | 16 (52.24 µM) | 4 (30 µM) | 2 (5.72 µM) * | |
23 | 0.03 (0.03 µM) | >8 (>7.30 µM) | 32 (104.48 µM) * | 0.125 (0.96 µM) | 4 (11.45 µM) * |
Cryptococcus Species | Isolate | MIC/MFC, [µM] | ||||
---|---|---|---|---|---|---|
Phendione | Cu-Phendione | Ag-Phendione | AgClO4 | Cu(ClO4)2.6H2O | ||
C. neoformans | 213 | 12.5/>100 | 3.125/50 | 1.56/25 | 1.56/>100 | >100/ND |
223 | 12.5/100 | 3.125/50 | 1.56/25 | 1.56/>100 | >100/ND | |
350 | 12.5/100 | 3.125/50 | 1.56/25 | 1.56/>100 | >100/ND | |
C. gattii | 27 | 12.5/>100 | 6.25/12.5 | 1.56/12.5 | 1.56/12.5 | >100/ND |
25 | 12.5/100 | 6.25/12.5 | 1.56/12.5 | 1.56/12.5 | >100/ND | |
23 | 12.5/>100 | 6.25/12.5 | 1.56/12.5 | 1.56/12.5 | >100/ND |
Cryptococcus Species | Isolate | MIC, [µM] | |
---|---|---|---|
Cu-Phendione | Ag-Phendione | ||
C. neoformans | ATCC 28957 | 1.56 | 0.19 |
H99 | 0.78 | 0.78 | |
T1444 | 0.78 | 0.78 | |
C. gattii | R265 | 0.19 | 0.19 |
Filters | Number of Violations | |||
---|---|---|---|---|
Ag-Phendione | Cu-Phendione | Amphotericin B | Fluconazole | |
Lipinski | 1 | 2 | 3 | 0 |
Ghose | 1 | 2 | 3 | 0 |
Veber | 0 | 0 | 1 | 0 |
Egan | 0 | 1 | 1 | 0 |
Muegge | 1 | 2 | 4 | 0 |
Pharmacokinetic Parameters | Test Compounds | |||
---|---|---|---|---|
Ag-Phendione | Cu-Phendione | Amphotericin B | Fluconazole | |
Inhibition of CYP1A2 | Yes | No | No | No |
Inhibition of CYP2C19 | Yes | No | No | Yes |
Inhibition of CYP2C9 | Yes | No | No | No |
Inhibition of CYP2D6 | No | No | No | No |
Inhibition of CYP3A4 | No | No | No | No |
Gastrointestinal absorption | High | High | Low | High |
Blood-brain barrier permeability | No | No | No | No |
P-glycoprotein substrate | Yes | Yes | Yes | Yes |
Log Kp (cm/s) | −7.97 | −8.21 | −11.94 | −7.92 |
Cryptococcus Species | Cu-Phendione | Ag-Phendione | ||
---|---|---|---|---|
Erythrocytes | G. mellonella Larvae | Erythrocytes | G. mellonella Larvae | |
C. gattii | >10 | >160 | >40 | >641 |
C. neoformans | >20 | >320 | >40 | >641 |
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Giovanini, L.; Casemiro, A.L.; Corrêa, L.S.; Mendes, M.; Mello, T.P.; Souza, L.O.P.; Wagner, L.G.; Fernandes, C.; Pereira, M.M.; de Souza, L.C.S.V.; et al. Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans. J. Fungi 2025, 11, 436. https://doi.org/10.3390/jof11060436
Giovanini L, Casemiro AL, Corrêa LS, Mendes M, Mello TP, Souza LOP, Wagner LG, Fernandes C, Pereira MM, de Souza LCSV, et al. Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans. Journal of Fungi. 2025; 11(6):436. https://doi.org/10.3390/jof11060436
Chicago/Turabian StyleGiovanini, Lucas, Ana Lucia Casemiro, Larissa S. Corrêa, Matheus Mendes, Thaís P. Mello, Lucieri O. P. Souza, Luis Gabriel Wagner, Christiane Fernandes, Matheus M. Pereira, Lais C. S. V. de Souza, and et al. 2025. "Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans" Journal of Fungi 11, no. 6: 436. https://doi.org/10.3390/jof11060436
APA StyleGiovanini, L., Casemiro, A. L., Corrêa, L. S., Mendes, M., Mello, T. P., Souza, L. O. P., Wagner, L. G., Fernandes, C., Pereira, M. M., de Souza, L. C. S. V., Baptista, A. R. S., de Moraes, J., McCann, M., Branquinha, M. H., & Santos, A. L. S. (2025). Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans. Journal of Fungi, 11(6), 436. https://doi.org/10.3390/jof11060436