Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans

Maho  Uchida; Gerry  McDermott; Modi  Wetzler; Mark A.  Le Gros; Markko  Myllys; Christian  Knoechel; Annelise E.  Barron; Carolyn A.  Larabell

doi:10.1073/pnas.0906145106

New Research In

Edited by John Kuriyan, University of California, Berkeley, CA, and approved September 23, 2009 (received for review June 4, 2009)

Abstract

The opportunistic pathogen Candida albicans can undergo phenotypic switching between a benign, unicellular phenotype and an invasive, multicellular form that causes candidiasis. Increasingly, strains of Candida are becoming resistant to antifungal drugs, making the treatment of candidiasis difficult, especially in immunocompromised or critically ill patients. Consequently, there is a pressing need to develop new drugs that circumvent fungal drug-resistance mechanisms. In this work we used soft X-ray tomography to image the subcellular changes that occur as a consequence of both phenotypic switching and of treating C. albicans with antifungal peptoids, a class of candidate therapeutics unaffected by drug resistance mechanisms. Peptoid treatment suppressed formation of the pathogenic hyphal phenotype and resulted in striking changes in cell and organelle morphology, most dramatically in the nucleus and nucleolus, and in the number, size, and location of lipidic bodies. In particular, peptoid treatment was seen to cause the inclusion of lipidic bodies into the nucleus.

Footnotes

¹To whom correspondence should be addressed. E-mail: carolyn.larabell{at}ucsf.edu
Author contributions: M.U., G.M., M.A.L.G., and C.A.L. designed research; M.U., G.M., M.W., M.A.L.G., and C.K. performed research; M.W. and A.E.B. designed and synthesized peptoids; M.M. developed analytical software; M.U., M.W., and M.M. analyzed data; and M.U., G.M., M.W., M.A.L.G., and C.A.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.