Evaluation Of ASP9726 On Glucan Synthase Inhibition From Echinocandin Susceptible And Resistant Fungi

Ref ID: 18751

Author:

P. Paderu, MS – Res Assoc.1, C. Jiménez-Ortigosa, PhD – Postdoc fellow 1, S. Akamatsu, PhD – Res Assoc. 2, S. Matsumoto, PhD – Res Assoc. 2, D. Perlin, PhD – Professor 1;

Author address:

1Publ. Hlth. Res. Inst, Newark, NJ, 2Astellas Pharma Inc., Ibaraki, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background and Objectives: The aim of this study was to assess the efficacy of a new glucan synthase inhibitor, ASP9726, on inhibition of β -(1,3)-glucan synthase activity from well-characterized echinocandin susceptible and resistant isolates of Candida glabrata and Aspergillus fumigatus. Methods: A total of eleven isolates were used in this study, including three echinocandin susceptible strains (Aspergillus fumigatus KU80α akuB, Candida albicans ATCC 90028 and Candida glabrata ATCC 90030) and eight C. glabrata clinical isolates harboring a range of mutations in the FKS hot spot regions and with elevated echinocandin MICs. Product-entrapped glucan synthase enzyme (GSE) from these isolates was assayed by measuring incorporation of radio-labeled glucose from UDP-[14C]-glucose into ethanol-insoluble polymeric products. Results and Conclusions: Glucan synthase was more sensitive to ASP9726 (2-165 fold) than to either caspofungin (CSF) or micafungin (MCF). The Aspergillus enzyme was more highly sensitive to ASP9726 than corresponding enzymes from C. albicans or C. glabrata. GSEs showed CSF, MCF and ASP9726 IC50 values of 8.95, 34.09 and 0.55, respectively for C. albicans, 13.12, 20.92 and 7.07 ng/ml, respectively, for C. glabrata, and 1.65, 1.65 and 0.01 ng/ml, respectively, for A. fumigatus. GSE from echinocandin resistant strains of C. glabrata with well-defined amino acid substitutions in either Fks1p or Fks2p showed reduced sensitivity to ASP9726 in accord with the behavior of MCF. ASP9726 and MCF showed greater sensitivity with fks mutant enzymes than CSF. The least sensitive enzymes were stratified by amino acid position and relative MIC, and included Fks1p F625S S629P and S663P. In the case of S663P, a prominent clinical echinocandin resistant mutant, ASP9726 was considerably more active than either CSF or MCF. Finally, Ki values of 3 and 60 ng/ml were determined for ASP9726 from A. fumigatus and C. albicans GSEs respectively. Overall, ASP9726 shows in vitro efficacy at the level of GSE that is comparable or better than MCF and superior to that of CSF; it warrants attention as a promising glucan synthase inhibitor.

Abstract Number: F-822

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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