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Campafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-09-03 , DOI: 10.1021/acs.jnatprod.0c00641 Bruno Perlatti 1 , Guy Harris 2 , Connie B Nichols 3 , Dulamini I Ekanayake 4 , J Andrew Alspaugh 3 , James B Gloer 4 , Gerald F Bills 1
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-09-03 , DOI: 10.1021/acs.jnatprod.0c00641 Bruno Perlatti 1 , Guy Harris 2 , Connie B Nichols 3 , Dulamini I Ekanayake 4 , J Andrew Alspaugh 3 , James B Gloer 4 , Gerald F Bills 1
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Campafungin A is a polyketide that was recognized in the Candida albicans fitness test due to its antiproliferative and antihyphal activity. Its mode of action was hypothesized to involve inhibition of a cAMP-dependent PKA pathway. The originally proposed structure appeared to require a polyketide assembled in a somewhat unusual fashion. However, structural characterization data were never formally published. This background stimulated a reinvestigation in which campafungin A and three closely related minor constituents were purified from fermentations of a strain of the ascomycete fungus Plenodomus enteroleucus. Labeling studies, along with extensive NMR analysis, enabled assignment of a revised structure consistent with conventional polyketide synthetic machinery. The structure elucidation of campafungin A and new analogues encountered in this study, designated here as campafungins B, C, and D, is presented, along with a proposed biosynthetic route. The antimicrobial spectrum was expanded to methicillin-resistant Staphylococcus aureus, Candida tropicalis, Candida glabrata, Cryptococcus neoformans, Aspergillus fumigatus, and Schizosaccharomyces pombe, with MICs ranging as low as 4–8 μg mL–1 in C. neoformans. Mode-of-action studies employing libraries of C. neoformans mutants indicated that multiple pathways were affected, but mutants in PKA/cAMP pathways were unaffected, indicating that the mode of action was distinct from that observed in C. albicans.
中文翻译：
Campafungins：白色念珠菌和新型隐球菌菌丝生长的抑制剂。
Campafungin A 是一种聚酮化合物，因其抗增殖和抗菌丝活性而在白色念珠菌适应性测试中得到认可。假设其作用方式涉及抑制 cAMP 依赖性 PKA 途径。最初提出的结构似乎需要以某种不寻常的方式组装的聚酮化合物。然而，结构表征数据从未正式发表。这一背景激发了一项重新研究，其中从子囊菌Plenodomus enteroleucus菌株的发酵中纯化了 Campafungin A 和三种密切相关的次要成分。标记研究以及广泛的核磁共振分析，使得能够分配与传统聚酮化合物合成机制一致的修改结构。介绍了 Campafungins A 和本研究中遇到的新类似物（此处称为 Campafungins B、C 和 D）的结构阐明，以及拟议的生物合成路线。抗菌谱扩展到耐甲氧西林金黄色葡萄球菌、热带念珠菌、光滑念珠菌、新型隐球菌、烟曲霉和粟酒裂殖酵母，新型念珠菌中的 MIC 低至 4–8 μg mL –1 。使用新型念珠菌突变体文库进行的作用模式研究表明，多种途径受到影响，但 PKA/cAMP 途径中的突变体不受影响，这表明作用模式与白色念珠菌中观察到的不同。
更新日期：2020-09-25
中文翻译：
Campafungins：白色念珠菌和新型隐球菌菌丝生长的抑制剂。
Campafungin A 是一种聚酮化合物，因其抗增殖和抗菌丝活性而在白色念珠菌适应性测试中得到认可。假设其作用方式涉及抑制 cAMP 依赖性 PKA 途径。最初提出的结构似乎需要以某种不寻常的方式组装的聚酮化合物。然而，结构表征数据从未正式发表。这一背景激发了一项重新研究，其中从子囊菌Plenodomus enteroleucus菌株的发酵中纯化了 Campafungin A 和三种密切相关的次要成分。标记研究以及广泛的核磁共振分析，使得能够分配与传统聚酮化合物合成机制一致的修改结构。介绍了 Campafungins A 和本研究中遇到的新类似物（此处称为 Campafungins B、C 和 D）的结构阐明，以及拟议的生物合成路线。抗菌谱扩展到耐甲氧西林金黄色葡萄球菌、热带念珠菌、光滑念珠菌、新型隐球菌、烟曲霉和粟酒裂殖酵母，新型念珠菌中的 MIC 低至 4–8 μg mL –1 。使用新型念珠菌突变体文库进行的作用模式研究表明，多种途径受到影响，但 PKA/cAMP 途径中的突变体不受影响，这表明作用模式与白色念珠菌中观察到的不同。
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