Manzoor Ahmad Malik, Shabir Ahmad Lone, Parveez Gull, Ovas Ahmad Dar, Mohmmad Younus Wani, Aijaz Ahmad* and Athar Adil Hashmi*
Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but alternative treatment strategies are promptly required.
Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates.
Results: A pyrimidine ring containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as rest of the combinations were indifferent. Interestingly, none of the combinations were antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies.
Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.
Candida albicans, Schiff base compounds, synergy, ergosterol biosynthesis, molecular docking
Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi-110025, Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi-110025, Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi-110025, Chemistry Department, Faculty of Science, University of Jeddah, P.O. Box 80327, Jeddah 21589, Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi-110025