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靶向必需GTP酶Obg以开发广谱抗生素。

Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics.

作者信息

Bonventre Josephine A, Zielke Ryszard A, Korotkov Konstantin V, Sikora Aleksandra E

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, 97330, United States of America.

Department of Molecular and Cellular Biochemistry, and Center for Structural Biology, University of Kentucky, Lexington, KY, 40536, United States of America.

出版信息

PLoS One. 2016 Feb 5;11(2):e0148222. doi: 10.1371/journal.pone.0148222. eCollection 2016.

DOI:10.1371/journal.pone.0148222
PMID:26848972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4743925/
Abstract

A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA), a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC). GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from GC, ObgGC. The assay was validated with a pilot screen of 40,000 compounds and achieved an average Z' value of 0.58 ± 0.02, which suggests a robust assay amenable to high-throughput screening. We developed secondary assessments for identified lead compounds that utilize the interaction between ObgGC and fluorescent guanine nucleotide analogs, mant-GTP and mant-GDP, and an ObgGC variant with multiple alterations in the G-domains that prevent nucleotide binding. To evaluate the broad-spectrum potential of ObgGC inhibitors, Obg proteins of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus were assessed using the colorimetric and fluorescence-based activity assays. These approaches can be useful in identifying broad-spectrum Obg inhibitors and advancing the therapeutic battle against multidrug resistant bacteria.

摘要

一种有前景的新型广谱抗生素开发的药物靶点是高度保守的小GTP酶Obg(YhbZ,CgtA),它是包括淋病奈瑟菌(GC)在内的所有细菌生存所必需的蛋白质。GC是淋病的病原体,淋病是一种常见的性传播疾病,会对生殖和新生儿健康造成严重后果。目前尚无预防性抗淋病疫苗,有效的抗生素治疗选择也越来越有限。为了满足对抗菌新策略的迫切需求,我们设计并优化了一种384孔GTP酶检测方法,以鉴定Obg的抑制剂,该方法以GC来源的Obg蛋白ObgGC为模型。通过对40000种化合物的初步筛选验证了该检测方法,平均Z'值为0.58±0.02,这表明该检测方法稳健,适用于高通量筛选。我们针对已鉴定的先导化合物开发了二级评估方法,该方法利用ObgGC与荧光鸟嘌呤核苷酸类似物mant-GTP和mant-GDP之间的相互作用,以及一种在G结构域有多处改变以阻止核苷酸结合的ObgGC变体。为了评估ObgGC抑制剂的广谱潜力,使用比色法和基于荧光的活性检测方法对肺炎克雷伯菌和耐甲氧西林金黄色葡萄球菌的Obg蛋白进行了评估。这些方法有助于鉴定广谱Obg抑制剂,并推动对抗多重耐药细菌的治疗斗争。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/b981b1d9d27a/pone.0148222.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/2d43aee187fb/pone.0148222.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/a567a7758f53/pone.0148222.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/69306b05d339/pone.0148222.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/b981b1d9d27a/pone.0148222.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/2d43aee187fb/pone.0148222.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/a567a7758f53/pone.0148222.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/69306b05d339/pone.0148222.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/4743925/b981b1d9d27a/pone.0148222.g004.jpg

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Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance.
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