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Antimicrobial Agents and Chemotherapy, July 2003, p. 2273-2282, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2273-2282.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Molecular Basis for Fungal Selectivity of Novel Antimitotic Compounds

Thomas Lila,1* Thomas E. Renau,1,{dagger} Lori Wilson,1 Jay Philips,1,{ddagger} Georges Natsoulis,1,§ M. Jamie Cope,|| William J. Watkins,1 and Jerry Buysse||

Essential Therapeutics, Mountain View, California 940431

Received 4 December 2002/ Returned for modification 17 January 2003/ Accepted 18 April 2003

Compounds that selectively disrupt fungal mitosis have proven to be effective in controlling agricultural pests, but no specific mitotic inhibitor is available for the treatment of systemic mycoses in mammalian hosts. In an effort to identify novel mitotic inhibitors, we used a cell-based screening strategy that exploited the hypersensitivity of a yeast {alpha}-tubulin mutant strain to growth inhibition by antimitotic agents. The compounds identified inhibited yeast nuclear division and included one structural class of compounds shown to be fungus specific. MC-305,904 and structural analogs inhibited fungal cell mitosis and inhibited the in vitro polymerization of fungal tubulin but did not block mammalian cell microtubule function or mammalian tubulin polymerization. Extensive analysis of yeast mutations that specifically alter sensitivity to MC-305,904 structural analogs suggested that compounds in the series bind to a site on fungal ß-tubulin near amino acid 198. Features of the proposed binding site explain the observed fungal tubulin specificity of the series and are consistent with structure-activity relationships among a library of related compounds.

* Corresponding author. Present address: Cytokinetics Inc., 280 E. Grand Ave., South San Francisco, CA 94080. Phone: (650) 624-3270. Fax: (650) 624-3010. E-mail: tlila{at}cytokinetics.com.

{dagger} Present address: Roche Bioscience Neurobiology Unit, Palo Alto, CA 94304.

{ddagger} Present address: Epigenomics, Inc., Seattle, WA 98101.

§ Present address: Iconix Pharmaceuticals, Mountain View, CA 94043.

|| Present address: Symyx Therapeutics, Santa Clara, CA 95051.

Antimicrobial Agents and Chemotherapy, July 2003, p. 2273-2282, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2273-2282.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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