The role of Cryptococcus neoformans histone deacetylase genes in the response to antifungal drugs, epigenetic modulators and to photodynamic therapy mediated by an aluminium phthalocyanine chloride nanoemulsion in vitro

• Published in: Journal of photochemistry and photobiology. B, Biology Vol. 216; p. 112131
• Main Authors: Ranjan, Kunal, Brandão, Fabiana, Morais, José Athayde V., Muehlmann, Luís Alexandre, Silva-Pereira, Ildinete, Bocca, Anamélia Lorenzetti, Matos, Larissa Fernandes, Poças-Fonseca, Marcio José
• Format: Journal Article
• Language: English
• Published: Switzerland Elsevier B.V 01.03.2021; Elsevier BV
• Subjects: Aluminum; Amphotericin B; Antifungal agents; Antifungal drugs; Azoles; Chlorides; Cryptococcus; Cryptococcus neoformans; Cryptococcus spp; Deoxyribonucleic acid; DNA; DNA methyltransferase; Drugs; Emulsions; Epigenetic modulators; Epigenetics; Fluconazole; Fungi; Fungicides; Genes; Heterocyclic compounds; Histone deacetylase; Histone deacetylase mutants; Histone methyltransferase; Histones; Immunomodulation; Inhibitors; Modulators; Mutants; Nanoemulsions; Pathogenicity; Pathogens; Photodynamic therapy; Public health; Sodium; Sodium butyrate; Sulfamethoxazole; Synergism; Trichostatin A; Virulence; Cryptococcus spp; Photodynamic therapy; Histone deacetylase mutants; Epigenetic modulators; Synergism; Antifungal drugs
• ISSN: 1011-1344; 1873-2682
• DOI: 10.1016/j.jphotobiol.2021.112131

Cryptococcus is a globally distributed fungal pathogen that primarily afflicts immunocompromised individuals. The therapeutic options are limited and include mostly amphotericin B or fluconazole, alone or in combination. The extensive usage of antifungals allowed the selection of resistant pathogens posing threats to global public health. Histone deacetylase genes are involved in Cryptococcus virulence, and in pathogenicity and resistance to azoles in Candida albicans. Aiming to assess whether histone deacetylase genes are involved in antifungal response and in synergistic drug interactions, we evaluated the activity of amphotericin B, fluconazole, sulfamethoxazole, sodium butyrate or trichostatin A (histone deacetylase inhibitors), and hydralazine or 5- aza-2′-deoxycytidine (DNA methyl-transferase inhibitors) against different Cryptococcus neoformans strains, C. neoformans histone deacetylase null mutants and Cryptococcus gattii NIH198. The drugs were employed alone or in different combinations. Fungal growth after photodynamic therapy mediated by an aluminium phthalocyanine chloride nanoemulsion, alone or in combination with the aforementioned drugs, was assessed for the C. neoformans HDAC null mutant strains. Our results showed that fluconazole was synergistic with sodium butyrate or with trichostatin A for the hda1Δ/hos2Δ double mutant strain. Sulfamethoxazole was synergistic with sodium butyrate or with hydralazine also for hda1Δ/hos2Δ. These results clearly indicate a link between HDAC impairment and drug sensitivity. Photodynamic therapy efficacy on controlling the growth of the HDAC mutant strains was increased by amphotericin B, fluconazole, sodium butyrate or hydralazine. This is the first study in Cryptococcus highlighting the combined effects of antifungal drugs, histone deacetylase or DNA methyltransferase inhibitors and photodynamic therapy in vitro. •Fluconazole resistant C. neoformans strains were more susceptible to HDAC inhibitors than the reference H99 strain.•Antifungal and epigenetic drugs acted synergistically against the C. neoformans HDAC genes deletion strains.•Our results established a clear link between HDAC impairment and increased drug susceptibility in Cryptococcus.•Amphotericin B, fluconazole, sodium butyrate, or hydralazine potentiated the PDT antimicrobial activity.