6. Conclusions

against three infectious forms: planktonic cells, biofilm formation, and preformed biofilm of C. neoformans and C. laurentii. The anti-biofilm activity of the tested compounds was in the order thymol > carvacrol > citral > eugenol = cinnamaldehyde > menthol. The three most potent compounds thymol, carvacrol, and citral showed best anti-biofilm activity at a much lower concentration against C. laurentii. In the presence of these potent compounds, assays revealed the absence of extracellular polymeric matrix, reduction in cellular density, and alteration in the surface morphology of biofilm cells. In addition they were the most efficient in terms of human safety in keratinocyte-Cryptococcus spp. co-culture infection model suggesting that thymol, carvacrol, and citral can be further exploited as cost-effective and nontoxic

The lectin pCramoll from Cratylia mollis, a native forage plant endemic to the semiarid region of Brazil (caatinga biome), showed an immunomodulatory effect and a synergism in combination with fluconazole, increasing the survival of animals with cryptococcosis caused by C. gattii and improving aspects of morbidity present

Thymol exhibited synergistic effects when combined with fluconazole against clinical species of Candida, enhancing the antifungal potential of the drug and decreasing the concentration required for the effect [172]. Zaidi et al. [173] found that methanolic extract of leaves of Ocimum sanctum in combination with fluconazole showed higher antifungal potential and synergistic activity against resistant

Candida spp. than methanolic extract or fluconazole when used alone.

improve drug effectiveness against topical candidiasis [174].

Essential oils were also recently proposed to increase drug effectiveness. Lavandula and Rosmarinus essential oils were selected as antiproliferative agents to compound lipid nanoparticles for clotrimazole delivery in treatment of Candida skin infections. Authors confirmed the potential anti-Candida activity of the selected oils due to their interaction with membrane permeabilization. In addition, in vitro studies against Candida albicans, Candida krusei, and Candida parapsilosis showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming that nanostructured lipid carriers (NLC) containing these essential oils represent a promising strategy to

A novel therapeutic strategy that has been adopted is photodynamic therapy (PDT). It is based on the interaction between a nontoxic photosensitizer and a safe source of visible light at a low intensity; the combination of these two factors in the presence of oxygen leads to the development of reactive oxygen species (ROS) which are toxic and cause oxidative damage to microorganism cells [175]. Curcumin associated with LED light was an efficient strategy against biofilms of C. dubliniensis isolates [176]. The uptake of CUR by yeast cells and its penetration through the biofilm were accompanied by confocal laser scanning microscopy. Daliri et al. [177] have assessed the effect of curcumin- and methyl blue-mediated PDT in combination with different laser exposure parameters on C. albicans colonies. They verified that the 460-nm laser in combination with CUR has the maximum antifungal

Although we have described herein many in vitro studies examining synergistic effects among potential antifungal biomolecules and traditional antifungal agents, the mechanisms underlying these synergistic effects are poorly understood. Randomized and controlled analyses have been performed with the objective of verifying the efficacy and risks of using traditional antifungal combinations; however, the results are poor and contradictory. High cost to conduct these strategies, reduced number of clinical cases, and the existence of confusing

variables are factors that contribute to the obtaining of vague and non-reproducible

anti-cryptococcal drugs.

Phytochemicals in Human Health

efficiency against C. albicans.

results.

246

in the progression of cryptococcosis [171].

The increase in Candida and Cryptococcus infections is alarming leading to high rates of morbidity and mortality worldwide. Concomitantly with the increase in fungal infections, species emerged, and the resistance phenomenon increased so that the available antifungal arsenal becomes irrelevant in the face of the problem. In addition, there are limitations manifested by some antifungal agents such as fungistatic character, severe toxicity, and renal dysfunction. Therefore, it is crucial to develop new drugs as alternative therapies that are potentially active against Cryptococcus and Candida. Plants are considered abundant and safe sources of phytochemicals endowed with many biological activities. Several polyphenols have been isolated and studied in relation to their anti-yeast and anti-virulence activities and may be useful in obtaining promising, efficient, and cost-effective drugs for the inhibition of Candida and Cryptococcus infections. Many phytosubstances are extremely effective in combination therapy with traditional or other phytochemicals, which can be further exploited to lead to novel drug therapies against recalcitrant infections.
