Pettit R K, Pettit G R, Hazen K C
Cancer Research Institute and Departments of Microbiology and Chemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
Antimicrob Agents Chemother. 1998 Nov;42(11):2961-5. doi: 10.1128/AAC.42.11.2961.
The biosynthetic peptide dolastatin 10 is currently in phase I and II cancer clinical trials. We evaluated the antifungal spectrum of dolastatin 10 and four structural modifications. In broth macrodilution assays, the peptides were fungicidal for American Type Culture Collection strains and clinical isolates (including fluconazole-resistant strains) of Cryptococcus neoformans but no other yeasts or filamentous fungi examined. Specificity for C. neoformans was also demonstrated in the solid-phase disk diffusion assay, and fungicidal activity was confirmed in time-kill experiments. For a methyl ester modification, the MICs at which 50 and 90% of 19 clinical isolates were inhibited (MIC50 and MIC90, respectively) were 0.195 and 0.39 microg/ml, respectively. The MFC50 (50% minimum fungicidal concentration) for this peptide was 0.39 microg/ml, and the MFC90 was 0.78 microg/ml. MICs and MFCs were identical or lower in the presence of human serum but increased with lowered pH. These peptides should be pursued as potential chemotherapeutics for C. neoformans, a leading cause of infection and mortality in immunocompromised patients.
生物合成肽多拉司他汀10目前正处于癌症I期和II期临床试验阶段。我们评估了多拉司他汀10及其四种结构修饰物的抗真菌谱。在肉汤稀释试验中，这些肽对美国典型培养物保藏中心的菌株以及新型隐球菌的临床分离株（包括耐氟康唑菌株）具有杀菌作用，但对所检测的其他酵母或丝状真菌无此作用。在固相纸片扩散试验中也证实了对新型隐球菌的特异性，并在时间-杀菌实验中确认了杀菌活性。对于一种甲酯修饰物，抑制19株临床分离株中50%和90%（分别为MIC50和MIC90）的最低抑菌浓度分别为0.195和0.39微克/毫升。该肽的MFC50（最低杀菌浓度的50%）为0.39微克/毫升，MFC90为0.78微克/毫升。在人血清存在的情况下，MIC和MFC相同或更低，但随着pH值降低而升高。这些肽应作为新型隐球菌潜在的化学治疗药物进行研究，新型隐球菌是免疫功能低下患者感染和死亡的主要原因。
