In vitro activities and postantifungal effects of the potent dolastatin 10derivative auristatin PHE

The pentapeptide dolavaline-valine-dolaisoleuine-dolaproine-phenylalanine-m ethyl ester (auristatin PHE) is a derivative of the anticancer drug dolasta tin 10 (dolavaline-valine-dolaisoleuine-dolaproine-dolaphenine). Broth micr odilution assays with a wide variety of yeast and filamentous fungal specie s demonstrated the specificity of auristatin PHE for Cryptococcus neoforman s and several species of Trichosporon. The duration of the postantifungal e ffect (PAFE) for C neoformans was determined for exposure times ranging fro m 30 min to 2 h. For the derivative, a PAFE was detectable after 45 min of exposure. The effect plateaued after I h of exposure, with a PAFE of approx imately 6.5 h at four or eight times the auristatin PHE MIC. In contrast, t here was no measurable PAFE after I h of exposure to dolastatin 10. Human s erum greatly prolonged the PAFE of auristatin PHE at eight times the MIC. A uristatin PHE arrested C. neoformans in the budding stage, possibly due to a tubulin-inhibitory action. Auristatin PHE has potential as a narrow-spect rum fungicidal agent and as a probe that can be used to study cryptococcal cell division.