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Antimicrobial Agents and Chemotherapy, December 2002, p. 3802-3808, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3802-3808.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effect of Auristatin PHE on Microtubule Integrity and Nuclear Localization in Cryptococcus neoformans

Tanja Woyke,1,2 Robert W. Roberson,3 George R. Pettit,1,4 Günther Winkelmann,2 and Robin K. Pettit1,5*

Cancer Research Institute,1 Departments of Microbiology,5 Chemistry and Biochemistry,4 Department of Plant Biology, Molecular and Cellular Biology Program, Arizona State University, Tempe, Arizona 85287,3 Eberhard Karls University Tübingen, 72076 Tübingen, Germany2

Received 20 March 2002/ Returned for modification 12 June 2002/ Accepted 19 August 2002

The mechanism of action of the fungicidal peptide auristatin PHE was investigated in Cryptococcus neoformans. Since auristatin PHE causes budding arrest in C. neoformans (T. Woyke, G. R. Pettit, G. Winkelmann, and R. K. Pettit, Antimicrob. Agents Chemother. 45:3580-3584, 2001), microtubule integrity and nuclear localization in auristatin PHE-treated cells were examined. Iterative deconvolution in conjunction with an optimized C. neoformans microtubule immunolabeling procedure enabled detailed visualization of the microtubule cytoskeleton in auristatin PHE-treated C. neoformans. The effect of auristatin PHE on C. neoformans microtubule organization was compared with that of the tubulin-binding agent nocodazole. Both drugs produced complete disruption first of cytoplasmic and then of spindle microtubules in a time- and concentration-dependent manner. Sub-MICs of auristatin PHE caused complete microtubule disruption within 4.5 h, while 1.5 times the nocodazole MIC was required for the same effect. For both drugs, disruption of microtubules was accompanied by blockage of nuclear migration and of nuclear and cellular division, resulting in cells arrested in a uninucleate, large-budded stage. Nocodazole and the linear peptide auristatin PHE are remarkably different in structure and spectrum of activity, yet on the cellular level, they have similar effects.

* Corresponding author. Mailing address: Cancer Research Institute, Arizona State University, Tempe, AZ 85287-2404. Phone: (480) 965-4907. Fax: (480) 965-8558. E-mail: pettitr{at}asu.edu.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3802-3808, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3802-3808.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Woyke, T., Berens, M. E., Hoelzinger, D. B., Pettit, G. R., Winkelmann, G., Pettit, R. K. (2004). Differential Gene Expression in Auristatin PHE-Treated Cryptococcus neoformans. Antimicrob. Agents Chemother. 48: 561-567 [Abstract] [Full Text]  


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