Molecular basis for fungal selectivity of novel antimitotic compounds.
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-305904 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-305904 structural analogs suggested that compounds in the series bind to a site on fungal beta-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.
Lila
Thomas
T
Essential Therapeutics, Mountain View, California 94043, USA. tlila@cytokinetics.com
Renau
Thomas E
TE
Wilson
Lori
L
Philips
Jay
J
Natsoulis
Georges
G
Cope
M Jamie
MJ
Watkins
William J
WJ
Buysse
Jerry
J
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011108:Polymers; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*; D014404:Tubulin / Q000235:genetics*
D000935:Antifungal Agents; D001562:Benzimidazoles; D011108:Polymers; D014404:Tubulin