Bills Gerald F, Platas Gonzalo, Overy David P, Collado Javier, Fillola Asunción, Jiménez María Rosa, Martín Jesús, del Val Antonio González, Vicente Francisca, Tormo J Rubén, Peláez Fernando, Calati Kathleen, Harris Guy, Parish Craig, Xu Deming, Roemer Terry
Centro de Investigación Básica, Merck, Sharp & Dohme de España S. A., Josefa Valcárcel 38, Madrid, E-28027, Spain.
Mycologia. 2009 Jul-Aug;101(4):449-72. doi: 10.3852/08-163.
Evaluation of fungal fermentation extracts with whole cell Candida albicans activity resulted in the identification of a novel class of isoxazolidinone-containing metabolites named parnafungins. Chemical-genetic profiling with the C. albicans fitness test identified the biochemical target as inhibition of polyadenosine polymerase, a component of the mRNA cleavage and polyadenylation complex. Parnafungins were discovered from fermentation extracts of fungi resembling F. larvarum isolated from plants, plant litter and lichens. Furthermore authentic strains of F. larvarum var. larvarum and F. larvarum var. rubrum could be induced to produce parnafungins and their degradation products in low titers. Relationships among strains of the F. larvarum complex (FLC), including parnafungin-producing strains, were examined by cladistic analyses of rDNA, mitochondrial rDNA, and two protein-coding genes, comparisons of antifungal activity and antifungal metabolite profiles, and morphological phenotypes. Integrated analyses of these data led to the conclusion that the diversity within the FLC exceeded the one-to-one correspondence between F. larvarum and its teleomorph Cosmospora aurantiicola. Based on multiple gene sequence analyses, strains of the FLC formed a monophyletic clade inclusive of the parnafungin-producing strains. The FLC, including newly discovered parnafungin-producing strains, could be resolved into at least six different lineages, possibly representing cryptic' species, of which one was not fully resolved from F. larvarum var. rubrum. Fusarium larvarum var. rubrum represents a species distinct from var. larvarum. Finally we report that two other species from the Hypocreales, Trichonectria rectipila and Cladobotryum pinarense, are able to produce parnafungins and their open-ring forms.
对具有白色念珠菌全细胞活性的真菌发酵提取物进行评估，结果鉴定出一类新型含异恶唑烷酮的代谢产物，命名为帕纳芬净。通过白色念珠菌适应性测试进行的化学遗传学分析确定其生化靶点为抑制聚腺苷酸聚合酶，这是mRNA切割和聚腺苷酸化复合体的一个组成部分。帕纳芬净是从类似于从植物、植物凋落物和地衣中分离出的幼虫镰刀菌的真菌发酵提取物中发现的。此外，幼虫镰刀菌变种幼虫和幼虫镰刀菌变种红变种的正宗菌株能够被诱导产生低滴度的帕纳芬净及其降解产物。通过对rDNA、线粒体rDNA和两个蛋白质编码基因进行分支分析、比较抗真菌活性和抗真菌代谢产物谱以及形态表型，研究了包括产帕纳芬净菌株在内的幼虫镰刀菌复合体（FLC）菌株之间的关系。对这些数据的综合分析得出结论，FLC内的多样性超过了幼虫镰刀菌与其有性型金橙孢壳之间的一一对应关系。基于多基因序列分析，FLC菌株形成了一个包含产帕纳芬净菌株的单系分支。包括新发现的产帕纳芬净菌株在内的FLC可以至少分为六个不同的谱系，可能代表隐性物种，其中一个与幼虫镰刀菌变种红变种尚未完全区分开来。幼虫镰刀菌变种红变种代表一个与变种幼虫不同的物种。最后，我们报告说，肉座菌目另外两个物种，直梗枝顶孢和松针枝顶孢，能够产生帕纳芬净及其开环形式。
