In vitro activities and postantifungal effects of the potent dolastatin 10 derivative auristatin PHE.
The pentapeptide dolavaline-valine-dolaisoleuine-dolaproine-phenylalanine-methyl ester (auristatin PHE) is a derivative of the anticancer drug dolastatin 10 (dolavaline-valine-dolaisoleuine-dolaproine-dolaphenine). Broth microdilution assays with a wide variety of yeast and filamentous fungal species demonstrated the specificity of auristatin PHE for Cryptococcus neoformans and several species of Trichosporon. The duration of the postantifungal effect (PAFE) for C. neoformans was determined for exposure times ranging from 30 min to 2 h. For the derivative, a PAFE was detectable after 45 min of exposure. The effect plateaued after 1 h of exposure, with a PAFE of approximately 6.5 h at four or eight times the auristatin PHE MIC. In contrast, there was no measurable PAFE after 1 h of exposure to dolastatin 10. Human serum greatly prolonged the PAFE of auristatin PHE at eight times the MIC. Auristatin PHE arrested C. neoformans in the budding stage, possibly due to a tubulin-inhibitory action. Auristatin PHE has potential as a narrow-spectrum fungicidal agent and as a probe that can be used to study cryptococcal cell division.
Woyke
T
T
Cancer Research Institute, Arizona State University, Tempe, Arizona 85287-2404, USA.
Pettit
G R
GR
Winkelmann
G
G
Pettit
R K
RK
D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D047630:Depsipeptides; D005658:Fungi / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D006801:Humans; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000494:pharmacology*; D013997:Time Factors
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D047630:Depsipeptides; D009842:Oligopeptides; C105791:soblidotin; C064570:dolastatin 10