DifferentialAspergillus lentulusEchinocandin Susceptibilities Are Fksp Independent

Abstract

The recently described species Aspergillus lentulus exhibits differential and reduced susceptibilities to echinocandins and other antifungal drugs in vitro. A. lentulus isolates overall are less susceptible to caspofungin, although they maintain susceptibility to anidulafungin and micafungin. Mutations or polymorphisms in fks, the gene encoding the catalytic subunit of ␤-1,3-glucan synthase, are known to confer decreased susceptibility to echinocandins in Candida spp. and Aspergillus fumigatus. The analysis of the A. lentulus fks sequence did not reveal a polymorphism at any of the known hot-spot regions of the gene. Caspofungin and micafungin kinetic inhibition profiles of the A. lentulus glucan synthase were comparable to those from susceptible A. fumigatus enzymes. Although the basal cell wall chitin levels in A. lentulus averaged 60% of those in A. fumigatus, echinocandin treatment promoted the increase of cell wall chitin in both organisms, indicating that A. lentulus displays a compensatory chitin response similar to that of A. fumigatus. The data suggest that differential echinocandin susceptibilities in A. lentulus are independent of the echinocandin target, Fksp, and they emphasize the potential that the drugs' capacity to inhibit the target enzyme is unequal at the cellular level.

Isavuconazole Activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, Emerging Fungal Pathogens with Reduced Azole Susceptibility

“…Efflux mechanisms in A. lentulus are unknown as yet; however, its Cyp51Ap homolog appears to be responsible for the decreased sensitivity to azoles (43). Prior studies evaluating A. lentulus echinocandin susceptibilities also suggest that nontarget characteristics, such as fungal cell wall composition, architecture, and/or hydrophobicity, may impact antifungal susceptibilities (44). The isavuconazole MICs of A. lentulus and N. udagawae isolates in this study, albeit low, varied (Table 1) and were comparable to the modal A. fumigatus MICs recently reported (26).…”

Role of Aspergillus lentulus 14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility

“…For triazole drugs, secondary resistance involving the acquisition of resistance in a susceptible strain accounts for all of the resistance described in A. fumigatus. On the other hand, the MICs of azole drugs for A. lentulus clinical samples are high, as are those of echinocandins and amphotericin B (3,9,41).…”

In Vitro Echinocandin Susceptibility of Aspergillus Isolates from Patients Enrolled in the Transplant-Associated Infection Surveillance Network

“…Because there are no breakpoints for any antifungal/mold combinations, we must rely on the available ECVs for determination of whether the MIC/MEC value is outside the wild-type distribution and could represent an isolate with a mutation that renders it resistant. There are also reports of species with elevated echinocandin MEC values, so proper species identification is essential (1,2,16).…”