Content Source ~ Journal of Clinical Microbiology ~ Rare and Emerging Opportunistic Fungal Pathogens
Current clinical management of infections by dimorphic fungal pathogens is limited to azole-class antifungal drugs and amphotericin B. While orally available, the azoles are not without host toxicity issues and the treatment course is lengthy for infections by dimorphic fungi. Development of resistance to azoles is not widespread, although treatment failures due to azole resistance have occurred.106-108 Unfortunately, the better tolerated echinocandin antifungals lack efficacy against the pathogenic-phase of the dimorphic fungal pathogens raising the need for alternative or second-line treatment options. While a number of strides have been made in repurposing existing drugs and development of new inhibitors of fungal growth, careful attention must be paid to challenges posed by dimorphic fungi. As the yeasts/spherules of the dimorphic fungi are the state present within the mammalian host, antimicrobial susceptibilities need to be performed with these pathogenic-phase cells, not the mycelia which has led to erroneous conclusions. Testing of the pathogenic-phase in vitro should follow recently optimized procedures as the CLSI methodology for yeasts is inadequate for the dimorphic fungi. Since yeast cells of the dimorphic fungi reside within host phagocytes, it is also advisable for in vitro tests to be followed with tests on drug effectiveness on intracellular yeasts, at least during initial drug development stages. The overall selectivity of antifungal drug candidates is
critical for progression of drugs through the development pipeline. Structure-guided rational design is one approach that has improved the selectivity of an azole structure (VT-1161). Many of the repurposed drugs have relatively high MICs (greater than 100 ug/mL) questioning their therapeutic utility, however if their selectivity is sufficiently high, formulations may be developed to facilitate
sufficiently high serum and tissue levels. Lower MICs have been found for drugs targeting the folate pathway, an isoniazid-hydrazone derivative, antiretroviral protease inhibitors, and the anti-cancer drug AR-12, all of which are expected to be reasonably well-tolerated by the mammalian host. Novel drugs with good in vitro MICs and good selectivity include thioredoxin-reductase inhibitors, an aminothiazole compound, and nikkomycin Z. Since nikkomycinZ targets an enzyme absent from the host, nikkomycin
has an excellent basis for high selectivity for fungi. In addition, nikkomycin Z has maintained antifungal
effectiveness against multiple dimorphic fungal pathogens in animal models of disease. While the current antifungal armament is limited, there are exciting prospects on the horizon for treating dimorphic fungal infections.