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Differential Aspergillus lentulus echinocandin susceptibilities are Fksp independent
Janet F Staab1, Jennifer Nielsen Kahn, Kieren A Marr
1Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross-1064, Baltimore, MD 21205, USA.
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 β-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.
Insights
Aspergillus lentulus shows reduced susceptibility to caspofungin but not other echinocandins. This difference in antifungal drug response is not due to mutations in the FKS gene, suggesting alternative mechanisms.
Area of Science:
- Mycology
- Antifungal Drug Discovery
- Molecular Biology
Background:
- Aspergillus lentulus, a recently identified fungal species, demonstrates varied in vitro susceptibility to echinocandin antifungal agents.
- Echinocandins target β-1,3-glucan synthase, an enzyme crucial for fungal cell wall synthesis.
- Mutations in the FKS gene, encoding a subunit of β-1,3-glucan synthase, are a known mechanism for echinocandin resistance in other fungi.
Purpose of the Study:
- To investigate the basis for differential echinocandin susceptibility in Aspergillus lentulus isolates.
- To determine if alterations in the FKS gene are responsible for reduced susceptibility to caspofungin.
- To compare the cellular response of A. lentulus to echinocandin treatment with that of a susceptible species, Aspergillus fumigatus.
Main Methods:
- Sequencing of the A. lentulus fks gene to identify polymorphisms in known hot-spot regions.
- Enzymatic assays to determine the kinetic inhibition profiles of caspofungin and micafungin against A. lentulus and A. fumigatus glucan synthase.
- Quantification of cell wall chitin levels in A. lentulus and A. fumigatus before and after echinocandin treatment.
Main Results:
- No polymorphisms were found in the hot-spot regions of the fks gene in A. lentulus.
- Kinetic inhibition profiles of caspofungin and micafungin on A. lentulus glucan synthase were similar to those of susceptible A. fumigatus.
- A. lentulus exhibited a compensatory increase in cell wall chitin upon echinocandin exposure, similar to A. fumigatus, despite lower basal chitin levels.
Conclusions:
- Differential echinocandin susceptibility in Aspergillus lentulus is independent of the FKS target enzyme.
- The findings suggest that the varying efficacy of echinocandins against A. lentulus may stem from unequal drug inhibition capacity at the cellular level.
- This study highlights the complexity of antifungal resistance mechanisms and the need for further investigation into drug-target interactions in emerging fungal pathogens.
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