- Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity
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The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- A nd 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell.
- Hewage, Achala N. D. Punchi,Yao, Huili,Nammalwar, Baskar,Gnanasekaran, Krishna Kumar,Lovell, Scott,Bunce, Richard A.,Eshelman, Kate,Phaniraj, Sahishna M.,Lee, Molly M.,Peterson, Blake R.,Battaile, Kevin P.,Reitz, Allen B.,Rivera, Mario
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supporting information
p. 8171 - 8184
(2019/06/13)
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- SMALL MOLECULE INHIBITORS OF THE BFRB:BFD INTERACTION
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The present technology provides compounds of Formula I and related methods for treating a bacterial infection as well as methods for inhibiting interaction of a bacterioferritin and a bacterioferritin-associated ferredoxin.
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Paragraph 0127; 0129; 0131
(2020/07/05)
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- ISOINDOLINE DERIVATIVES FOR USE AS AMPK ACTIVATORS
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The present invention refers to isoindoline-1,3-dionic derivatives, able to activate efficaciously the AMPK enzymatic complex, for use in the prophylaxis and therapeutic treatment of diseases and disorders in particular metabolic disorders, such as diabet
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Page/Page column 15-16
(2018/11/10)
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- Isoindole-1,3-dione derivatives as RSK2 inhibitors: Synthesis, molecular docking simulation and SAR analysis
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RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our previous study. Some compounds were confirmed to be moderately potent RSK2 inhibitors with IC50 values of about 0.5 μM. Structure-activity relationship analysis and binding mode studies by molecular docking were performed.
- Zhou, Wei,Li, Shiliang,Lu, Weiqiang,Yuan, Jun,Xu, Yufang,Li, Honglin,Huang, Jin,Zhao, Zhenjiang
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p. 292 - 296
(2016/03/01)
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