Planta Med 2014; 80 - PH8
DOI: 10.1055/s-0034-1382615

Discovery of natural products that enhance the activity of the antifungal drug caspofungin

S Tripathi 1, D Levin 2, Q Feng 1, XC Li 1, M Jacob 1, A Clark 1, A Agarwal 1
  • 1National Center for Natural Products Research, University of Mississippi, University, MS 38655
  • 2Department of Molecular and Cell Biology, Boston University, Boston, MA 02118

The antifungal drug caspofungin (CPF), although potent and well-tolerated, has a narrow spectrum of activity and drug resistance is a problem. Our approach is to improve CPF activity by altering the fungal cell wall integrity pathway (CWIP) involved in adaptation to cell wall damage exerted by CPF. Since the CWIP is regulated by the transcription factor Rlm1, this pathway can be monitored with a lacZ reporter driven by Rlm1-responsive elements. In this study, using this assay in a high throughput format, we have screened 880 compounds from our in-house collection, and identified 43 CWIP inhibitors and 16 CWIP inducers. Among the CWIP inhibitors, 3 classes of compounds were identified (sesquiterpene quinone, aminoquinoline, and triterpenoid glycoside) that improved CPF activity in Candida albicans. The sesquiterpene quinone, puupehenone (PUUP) also improved CPF potency in a CPF-resistant clinical isolate of C. albicans. In the CPF-insensitive pathogen, Cryptococcus neoformans, PUUP+CPF demonstrated fungicidal activity. Among the CWIP inducers, a quinoline alkaloid enhanced CPF activity in C. neoformans. Transcript profiling studies on PUUP+CPF revealed that CWIP genes that were strongly induced by CPF alone were not induced by CPF+PUUP. We also showed that PUUP targets Hsp90 and inhibits the CWIP by regulating the kinase Mpk1, which is an Hsp90 client protein. Our work reveals that compounds that alter the CWIP will be useful in combination therapy with CPF.