Effect of Curcumin Pretreatment on the Susceptibility of Cryptococcus neoformans to Photodynamic Therapy Mediated by Aluminum Phthalocyanine in Nanoemulsion

<b><b>Background/Objectives:</b></b> Curcumin has antimicrobial activity, and its mechanism of action involves changing histone acetylation. Our group has shown that histone deacetylases (HDACs) inhibitors increase the sensibility of <i>Cryptococcus neoformans</i> to certain antifungal treatments. Therefore, the aim of this work was to investigate whether curcumin pretreatment increases the effect of photodynamic therapy (PDT) mediated by aluminum phthalocyanine in nanoemulsion (AlPc-NE) against <i>C. neoformans</i>. <b>Methods:</b> The minimum inhibitory concentrations (MIC) of AlPc-NE and curcumin, along with the 72-h growth curve of cells exposed to the combined treatments, were evaluated in the <i>C. neoformans</i> reference strain H99. Additionally, further analysis was performed using HDAC gene deletion mutant strains, <i>hda1</i>Δ and <i>hos2</i>Δ. <b>Results:</b> Curcumin reduces the effect of PDT on <i>C. neoformans</i> reference strain H99, likely due to its antioxidant properties. In the <i>hda1Δ</i> strain, 50% MIC of curcumin reduced the effect of PDT, but this effect was not observed in response to 75% MIC of curcumin. Conversely, in the <i>hos2</i>Δ strain, pretreatment with curcumin at 75% MIC enhanced the efficacy of PDT in combination with 50% MIC of AlPc-NE. <b>Conclusions:</b> These results indicate that curcumin inhibits <i>C. neoformans</i>. Moreover, at lower concentrations, curcumin protects cells against oxidant damage, while at higher concentrations, it may trigger epigenetic mechanisms that compromise cell viability. In conclusion, both curcumin and PDT are active against <i>C. neoformans</i>, with HDACs affecting their efficacy, and the effectiveness of the combined treatment depends on the concentration of both curcumin and AlPc-NE.