Integrated Antimicrobial Drug Discovery Scheme for Multidrug Resistant Bacteria

针对多重耐药细菌的综合抗菌药物发现方案

基本信息

批准号：
7876892
负责人：
ZOLTAN N. OLTVAI
金额：
$ 54.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-15 至 2011-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7876892
关键词：
Address Antibiotics Antimicrobial Effect Applied Research Bacillus anthracis Bacteria Bacterial Drug Resistance Base Sequence Biochemical Pathway Biological Products Biotechnology Bioterrorism Categories Cell Survival Combined Antibiotics Complex Development Diet Drug Design Drug resistance Engineering Enzymes Equilibrium Francisella tularensis Future Gene Deletion Genome Genomics Goals Growth Hospitals In Vitro Infection Lethal Genes Medical Metabolic Metabolism Modality Modeling Molecular Molecular Target Multi-Drug Resistance Physicians Population Proteins Pseudomonas Pseudomonas aeruginosa Public Health Research Research Personnel Scheme Scientist Screening procedure Series Small Molecule Chemical Library Staphylococcus aureus System Terrorism Testing Time United States Yersinia pestis antimicrobial antimicrobial drug base drug discovery drug resistant bacteria experience experimental analysis inhibitor/antagonist meetings multidisciplinary mutant novel pathogen pathogenic bacteria programs reconstruction small molecule success virtual

项目摘要

DESCRIPTION (provided by applicant): The threat of multi-drug resistant bacteria as bioterrorism agents, but also the increasing drug resistance of pathogens in a hospital setting, poses a serious and potentially devastating medical problem that requires conceptually new treatment modalities using novel antibiotics. To meet this need, we propose an applied research program that aims to develop and experimentally validate an integrated antimicrobial drug discovery scheme. In particular, as metabolic activity is a key integrator of all prokaryotic functions, through the analysis of their system-level metabolic organization we will identify those bacterial enzymes whose activity, alone or in combination, is required at all times for the viability of three Category A bacterial bioterrorism agents and two important pathogenic bacteria with significant problem of multidrug resistance in the hospital setting. We will then identify and experimentally validate a series of small-molecule inhibitors against these enzyme targets, which can subsequently serve as structural leads for the development of new antibiotics. The proposed project will be carried out in a framework of a well-established, tightly integrated multidisciplinary effort among research groups of a molecular biologist and physician-scientist with experience in the theoretical and experimental analysis of bacterial metabolic networks (Z. N. Oltvai), a theoretical physicist with experience in assessing the structural and dynamical features of complex networks (A.-L. Barabasi), a biotechnology company with extensive experience with genome annotation, metabolic reconstruction and corresponding wet lab confirmation (Integrated Genomics, Inc.), and an organic and computational chemist with extensive experience in computational drug design and development (O. Wiest). The project will be further aided by the active computational and experimental support of four Consultants.

描述（由申请人提供）：多药耐药细菌作为生物恐怖剂的威胁，以及医院环境中病原体的耐药性的日益增加，带来了严重且潜在的毁灭性医学问题，需要使用新型抗生素在概念上进行概念上的新治疗方式。为了满足这种需求，我们提出了一项应用研究计划，旨在开发和实验验证综合的抗菌药物发现方案。特别是，由于代谢活性是所有原核功能的关键集成剂，通过分析其系统水平的代谢组织，我们将确定这些细菌酶的单独或组合需要的细菌酶，对于三类细菌生物恐怖剂和两个重要的病原细菌的可行性始终都是可行性，并且具有多大的病原体耐药性。然后，我们将识别并实验验证一系列针对这些酶靶标的一系列小分子抑制剂，随后可以作为开发新抗生素的结构铅。拟议的项目将在一个框架内进行，由分子生物学家和医师科学家的研究小组之间的研究小组进行，具有在细菌代谢网络的理论和实验分析中经验的经验（Z. N. Oltvai）（Z. N. Oltvai），具有理论上的生理学家，具有结构性和动态性的特征（A. A.）。具有丰富基因组注释，代谢重建和相应的湿实验室确认（Integrated Genomics，Inc。）的公司，以及具有丰富经验的计算药物设计和开发经验（O. Wiest）的有机和计算化学家。四个顾问的主动计算和实验支持将进一步帮助该项目。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays.

DOI：
10.1016/j.bmc.2010.05.060
发表时间：
2010-07-15
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY
影响因子：
3.5
作者：
Henriksen, S. T.;Liu, J.;Estiu, G.;Oltvai, Z. N.;Wiest, O.
通讯作者：
Wiest, O.

Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited.

DOI：
10.1186/1752-0509-4-58
发表时间：
2010-05-06
期刊：
BMC systems biology
影响因子：
0
作者：
Vazquez A;Liu J;Zhou Y;Oltvai ZN
通讯作者：
Oltvai ZN

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology.

DOI：
10.1371/journal.pone.0019538
发表时间：
2011-04-29
期刊：
PloS one
影响因子：
3.7
作者：
Vazquez A;Oltvai ZN
通讯作者：
Oltvai ZN

Impact of the solvent capacity constraint on E. coli metabolism.

DOI：
10.1186/1752-0509-2-7
发表时间：
2008-01-23
期刊：
BMC SYSTEMS BIOLOGY
影响因子：
0
作者：
Vazquez, Alexei;Beg, Qasim K.;deMenezes, Marcio A.;Ernst, Jason;Bar-Joseph, Ziv;Barabasi, Albert-Loszlo;Boros, Laszlo G.;Oltvai, Zoltan N.
通讯作者：
Oltvai, Zoltan N.

Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation.