Lohse Matthew B, Ennis Craig L, Hartooni Nairi, Johnson Alexander D, Nobile Clarissa J
Department of Microbiology and Immunology, University of California-San Francisco, San Francisco, CA 94158, USA.
Department of Biology, BioSynesis, Inc., San Francisco, CA 94114, USA.
J Fungi (Basel). 2020 Dec 27;7(1):9. doi: 10.3390/jof7010009.
The human fungal pathogen can form biofilms on biotic and abiotic surfaces, which are inherently resistant to antifungal drugs. We screened the Chembridge Small Molecule Diversity library containing 30,000 "drug-like" small molecules and identified 45 compounds that inhibited biofilm formation. These 45 compounds were then tested for their abilities to disrupt mature biofilms and for combinatorial interactions with fluconazole, amphotericin B, and caspofungin, the three antifungal drugs most commonly prescribed to treat infections. In the end, we identified one compound that moderately disrupted biofilm formation on its own and four compounds that moderately inhibited biofilm formation and/or moderately disrupted mature biofilms only in combination with either caspofungin or fluconazole. No combinatorial interactions were observed between the compounds and amphotericin B. As members of a diversity library, the identified compounds contain "drug-like" chemical backbones, thus even seemingly "weak hits" could represent promising chemical starting points for the development and the optimization of new classes of therapeutics designed to target biofilms.
这种人类真菌病原体可在生物和非生物表面形成生物膜，而生物膜本身对抗真菌药物具有抗性。我们筛选了包含30000种“类药物”小分子的Chembridge小分子多样性文库，鉴定出45种抑制生物膜形成的化合物。然后测试了这45种化合物破坏成熟生物膜的能力以及与氟康唑、两性霉素B和卡泊芬净（治疗感染最常用的三种抗真菌药物）的联合相互作用。最终，我们鉴定出一种自身能适度破坏生物膜形成的化合物，以及四种仅与卡泊芬净或氟康唑联合使用时能适度抑制生物膜形成和/或适度破坏成熟生物膜的化合物。未观察到这些化合物与两性霉素B之间存在联合相互作用。作为多样性文库的成员，鉴定出的化合物含有“类药物”化学骨架，因此即使看似“弱活性化合物”也可能代表开发和优化旨在靶向生物膜的新型治疗药物的有前景的化学起始点。
