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金黄色葡萄球菌药物外排泵 NorA 抑制作用的结构基础。

Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus.

机构信息

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA.

Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

出版信息

Nat Chem Biol. 2022 Jul;18(7):706-712. doi: 10.1038/s41589-022-00994-9. Epub 2022 Mar 31.

DOI:10.1038/s41589-022-00994-9
PMID:35361990
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9246859/
Abstract

Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.

摘要

膜蛋白外排泵通过将结构不同的化合物排出细胞外并降低其细胞内浓度，从而赋予抗生素耐药性。然而，目前还没有临床批准的药物来抑制外排泵，而这些药物可以增强因药物外排而失效的现有抗生素的疗效。在这里，我们鉴定了抑制耐甲氧西林金黄色葡萄球菌 (MRSA) 中喹诺酮转运蛋白 NorA 的合成抗原结合片段 (Fab)。使用冷冻电子显微镜确定的两个 NorA-Fab 复合物结构揭示了 Fab 环深深插入 NorA 的底物结合口袋中。该环上的一个精氨酸残基与两个相邻的天冬氨酸和谷氨酸残基相互作用，这些残基对于 MRSA 中 NorA 介导的抗生素耐药性至关重要。Fab 环的肽模拟物以亚微摩尔的效力抑制 NorA，并与抗生素诺氟沙星联合消除 MRSA 的生长。这些发现确立了一类肽抑制剂，它们通过靶向 NorA 中的必需残基来阻断 MRSA 中的抗生素外排，而无需膜通透性。

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