An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

Abstract

Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies.

Keywords: Candida; antifungal drugs; antimicrobials; candidiasis; non-conventional therapeutics; phytotherapeutics and probiotics; resistance to antifungals.

Figure 1

Representative examples of the antifungals currently available to treat candidiasis. Chemical structure of representative examples of antifungals (azoles, echinocandins, polyenes and fluoropyrimidines) available, with the class of the drug being highlighted in black bold while the name of the drugs is shown in green. The nitrogen-based ring that distinguishes imidazoles (clotrimazole) from triazoles (fluconazole) is highlighted in blue.

Figure 2

Schematic representation of the known mechanisms of action of the different classes of antifungals available for treatment of candidiasis. 5-FU—5-fluorouracil; 5-FUMP—5-fluorouridine monophosphate; FdUMP—5-fluorodeoxyuridine monophosphate; FUTP—5-fluorouridine triphosphate.

Figure 3

Schematic representation of regulatory associations between regulators involved in azole resistance and genes encoding multidrug resistance efflux pumps demonstrated to be involved in azole resistance in Candida spp. The information concerning the regulatory associations between transcription factor and target genes was retrieved from the PathoYeastract database [84]. Although ABC-MDR and MFS-MDR transporters involved in azole resistance in C. krusei and C. tropicalis had been identified, until so far the regulators of these genes remain to be characterized.