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    • Echinocandin resistance is systematically associated with

    2024-03-28

    Echinocandin resistance is systematically associated with point mutations in either FSK1 or FSK2 genes [7], [104]. These mutations are located in two different not spot regions of these genes named HS1 and HS2. Hot spot mutations have been reported in C. albicans, C. glabrata, C. tropicalis, C. krusei, Scedosporium apiospermum and A. fumigatus[7], [104]. Such mutations alter the kinetics of the glucan synthase resulting in significantly higher inhibitory concentrations and inhibition constant [125], [126]. The most common mechanism of resistance to pyrimidine analogs (5FC) is a point mutation in the FUR1 gene. This mutation leads to complete resistance to 5FC and 5FU in fungi [7]. A second point mutation in the gene encoding for cytosine deaminase results in 5FC resistance in many Candida strains [127]. The third mechanism by which fungal pathogens can develop resistance against antifungal agents is by modifying metabolic pathways leading to loss or strong decrease of their specific function. Alteration of the last steps of the ergosterol biosynthesis through inactivation of the ERG3 gene results in no production of toxic methylated sterols that lead to cross resistance to all azole drugs [104]. Furthermore, mutations in non-essential genes of this pathway (ERG3, ERG6, ERG24 and ERG2) also lead to a decrease, or even total absence, of ergosterol in plasma membrane [128]. As reported above mutations in the FUR1 gene decrease the conversion of 5FU into toxic metabolites able to enter the cytosine metabolism and exert their toxic effect. Downregulation of FUR1 also decreased 5FC susceptibility. A 4-fold lower expression of this gene leads to total resistance to 5FC in C. glabrata species [7]. In the recent years reports on novel resistance profiles have been reported and the most problematic is the development of simultaneous resistance to at least two different daminozide receptor of antifungal agents (a condition known as multidrug resistance, MDR) [104]. Loss of function point mutations or simultaneous mutations in ERG2, ERG3, ERG5 and ERG11 result in MDR to azoles and amphotericin B in Candida species [104], [128]. Resistance to echinocandins (e.g. caspofungin) and azoles has also been reported. The resistance mechanisms seem to be due to combinations of mutations in the FSK2 gene and ABC transporters upregulation [104]. Although not very common, a few cases of resistance for more than two drug classes have been recently described in C. albicans and C. lusitaniae isolates [144]. The current trends show that the highest proportion of resistant isolates is from C. glabrata[9] representing more than 10% of total isolates in the European Union and more than 20% in the USA. Such isolates show high resistance to azoles (fluconazole and voriconazole) as well as to echinocandins. New infections due to Fusarium spp., Zygomycetes and azole- and echinocandins-resistant C. glabrata isolates are being more frequently observed.
    Antifungal pipeline Despite it is clear that there is an urgent need for new antifungal agents [8], [9], [10], [96], [104] in their complex development as well as the lack of investment are responsible for a limited drug development pipeline. However, antifungal development has been recently boosted by two Acts from the US Administration. The first is GAIN (Generating Antibiotic Incentives Now) that provides a fast track description and priority review by FDA to QIDP (Qualified Infections Disease Products) as well as a 5year extension of market exclusivity. The second is the Orphan Drug Act that encourages the development of drugs for rare diseases, including several invasive mycoses, and provides 7year market exclusivity. The new antifungal drugs should improve fungal disease mortality, show better fungicidal activity, extend the spectrum of activity against drug-resistant fungi and rare molds such as Scedosporium spp., improve the pharmacokinetics and pharmacodynamics, reduce/avoid host toxicity, cause few drug-drug interactions, and act by new, selective and different mechanisms of action. Indeed, no new classes of antifungals have been approved since 2006 when the FDA and the EMA (European Medicines Agency) authorized anidulafungin.