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.

Plant-Derived Substances in the Fight Against Infections Caused by Candida Species

“…The best-known drug from this group—AMB—is also effective against Candida spp. biofilm [ 57 ] and is often used in a safer liposome-encapsulated form; however, this form is also more expensive, making this drug medication for second-line therapy [ 65 ]. Moreover, nystatin or natamycin are useful only for the treatment of superficial infections [ 60 , 66 ].…”

“…Although rare, the resistance to polyenes was described for some Candida strains isolated from infected patients, with fungal cells overcoming polyene action by reducing the amount of ergosterol in the plasma membrane. This is implemented by some defects in the ERG3 and ERG6 genes encoding enzymes of ergosterol biosynthesis, or its substitution by non-ergosterol cytoplasmic sterols and lipids [ 65 , 67 ].…”

“…This results in the formation of toxic sterols (14-α-methylsterols), placed loosely within lipid bilayers and decreasing tightness and stability of fungal cell membrane [ 59 ]. This group of synthetic fungistatic drugs includes imidazoles (clotrimazole, econazole, miconazole and ketoconazole), used primarily for the treatment of superficial infections, and triazoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) preferred for fighting against invasive candidiasis [ 65 , 66 , 68 ]. Although generally well-tolerated, azoles also have several limitations, such as hepatoxicity, mainly observed for clotrimazole and miconazole [ 69 ].…”

“…Additionally, the emerging resistance to this group of drugs among isolates of Candida spp., especially C. auris , C. parapsilosis and C. tropicalis is currently observed [ 54 , 70 ] as a consequence of the massive preventive application of fluconazole [ 71 , 72 ] and common use of agricultural fungicides, structurally similar to azoles [ 73 ]. The resistance relies on the mutations or overexpression of ERG11 and ERG3 genes, which lead to increased tolerance to methylated sterols and overexpression of drug-efflux pumps that transport azoles outside of the fungal cell [ 65 , 67 ].…”

“…The most commonly used is 5-fluorocytosine that enters the fungal cell via the transport mechanism based on cytosine permease, and inside the fungal cell it is converted to 5-fluorouracil that, after phosphorylation, can inhibit thymidylate synthase, essential during DNA replication. After a further phosphorylation step, the compound formed is embedded in the RNA structure, causing premature chain termination [ 62 , 65 ]. The disadvantages of such treatment are the adverse side effects of using 5-fluorocytosine, including the hepatic impairment, interference with bone marrow function and rapid development of resistance by Candida species [ 68 ].…”