Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, Tampa, FL 33620, USA.
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.
Mar Drugs. 2012 Apr;10(4):762-774. doi: 10.3390/md10040762. Epub 2012 Mar 28.
Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC(90) of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC(90) of 437 µM, representing a 90% inhibition therapeutic index (TI(90) = IC(90) A459/IC(90)P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM).
最近的基因组研究表明，真菌可以拥有基因簇，用于产生以前未观察到的次生代谢产物。激活这些被削弱或沉默的基因，以获得已知化合物的更高产量或全新的化合物，一直是一个相当有吸引力的话题。在我们努力发现对抗传染病（包括疟疾和耐甲氧西林金黄色葡萄球菌（MRSA））有效的新型化学型的过程中，我们分离出一种海洋真菌 Leucostoma persoonii，它能产生具有生物活性的细胞色素酮。用于激活次生代谢基因的表观遗传修饰剂导致已知细胞色素酮 B（1，360%）、C（2，580%）和 E（3，890%）的产量增加，以及以前未描述的细胞色素酮 R（4）的产量增加。细胞色素酮 E 是最具生物活性的，对疟原虫的 IC90 为 13 µM，对 A549 的细胞毒性 IC90 为 437 µM，代表 90%的抑制治疗指数（TI90 = IC90A459/IC90P。falciparum）为 33。此外，细胞色素酮 E 对 MRSA 有效，最小抑菌浓度（MIC）为 72 µM，对 MRSA 生物膜的抑制作用约为其一半（最低生物膜清除计数，MBEC90 为 39 µM）。
