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Function of MVFR in Pseudomonas Aeruginosa Virulence

MVFR 在铜绿假单胞菌毒力中的作用

基本信息

批准号：
8528902
负责人：
LAURENCE G RAHME
金额：
$ 47.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-21 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528902
关键词：
Acute Animal Model Animals Anthranilic Acids Anti-Infective Agents Antibiotic Resistance Antibiotics Attenuated Bacteria Bacterial Infections Benzamides Benzimidazoles Binding Biochemical Burn injury Bypass Cells Chemicals Chronic Communication DNA DNA Binding Data Development Emerging Communicable Diseases Feedback Figs - dietary Funding Generations Genes Glossary Goals Gram-Negative Bacteria Growth Health Hospitals Human Incidence Infection Intensive Care Units Laboratories Lead Ligand Binding Ligands Liquid Chromatography Magnetic Resonance Imaging Mammals Mediating Metabolism Microbe Modeling Molecular Genetics Molecular Target Molecular Weight Multi-Drug Resistance Mus Operon Oxides Pathogenesis Pathway interactions Play Population Population Density Process Production Property Protein Region Pseudomonas aeruginosa Public Health Refractory Regulation Regulon Relapse Research Resistance Role Signal Pathway Signal Transduction Spectrometry Structure Structure-Activity Relationship System Testing Text Therapeutic Virulence Virulence Factors Work absorption antimicrobial antimicrobial drug benzimidazole biodefense combat commensal microbes density drug discovery genetic analysis high throughput screening improved in vivo inhibitor/antagonist innovation insight intercellular communication iron oxide killings liquid chromatography mass spectrometry mutant novel novel strategies pathogen pressure prevent promoter public health relevance quorum sensing small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): New approaches to antimicrobial drug discovery are urgently needed to combat untreatable infections caused by antibiotic resistant or persistent, antibiotic tolerant, bacteria. The long-term goal of this proposal is to develop novel therapy options that may prevent or reduce the complications of human bacterial acute and chronic or relapsing infections, and that could serve as alternatives or adjuncts to antibiotics. To achieve a paradigm shift in antimicrobial therapy, we propose to develop inhibitors of bacterial signaling pathways that control bacterial virulence and antibiotic tolerance mechanisms. Population density-dependent signaling, generally referred to as quorum sensing (QS), is one such mechanism. QS regulates multiple aspects of virulence. It is important for the development of acute infections and as recently discovered for the formation of antibiotic-tolerant cell populations, a process underlying pathogen persistence in chronic infections. This renewal application will test the hypothesis that novel inhibitors of QS, previously identified by us, can lead to the development of highly potent compounds with anti-infective activity in vivo. We will test this hypothesis by employing Pseudomonas aeruginosa, a recalcitrant Gram-negative bacterium that defies eradication by antibiotics and exemplifies current problematic pathogens in hospitals and intensive care units. In the last funding cycle, we demonstrated that P. aeruginosa pathogenesis can be disrupted in vivo by pharmacologically interfering with the multiple virulence factor regulator (MvfR) regulon, a component of QS circuitry that controls virulence and, as we recently discovered, the formation of antibiotic tolerant cells. We elucidated the mechanism of MvfR regulon activation and identified several small chemical compounds that inhibit the MvfR transcription factor and/or interfere with MvfR regulon activity in vivo. Using these chemical compounds, we will test our hypothesis through three Specific Aims: 1) To study the mechanisms of action of the candidate compounds using biochemical, mass spectrometric, and molecular genetic analyses. 2) To improve the most potent QS inhibitors through structure-activity relationship (SAR) studies. 3) To validate the in vivo efficacy of SAR-improved inhibitors in attenuating P. aeruginosa infection in suitable animal models. QS signaling circuits are evolutionarily conserved and play central roles in modulating virulence mechanisms in many different human pathogens. Therefore, by selectively interfering with QS, our data should yield paradigmatic insights that will be generally relevant for the development of new classes of anti-infectives that could limit development of multi-drug resistance and antibiotic tolerance in bacterial pathogens, while preserving beneficial commensal bacteria. Moreover, the study and inhibition of mechanisms involved in antibiotic tolerance could have a major impact on elucidating this unresolved phenomenon, as well as enabling the discovery of the first probe compounds targeted against antibiotic tolerant cells.

描述（由申请人提供）：迫切需要抗菌药物发现的新方法，以对抗由抗生素耐药或持久性抗生素耐药细菌引起的无法治疗的感染。这项提议的长期目标是开发新的治疗方案，以预防或减少人类细菌急性、慢性或复发性感染的并发症，并可作为抗生素的替代品或辅助手段。为了实现抗菌治疗的范式转变，我们建议开发控制细菌毒力和抗生素耐受性机制的细菌信号通路抑制剂。种群密度相关的信号，通常被称为群体感应（QS），就是这样一种机制。QS调节多个方面的毒力。它对急性感染的发展和最近发现的抗生素耐受细胞群的形成很重要，这是慢性感染中病原体持续存在的一个过程。这一更新申请将验证我们之前发现的新型QS抑制剂可以导致体内抗感染活性的高效化合物的开发的假设。我们将采用铜绿假单胞菌来检验这一假设，铜绿假单胞菌是一种顽固性革兰氏阴性细菌，无法被抗生素根除，是目前医院和重症监护病房中存在问题的病原体的典型。在上一个资助周期中，我们证明了铜绿假单胞菌的发病机制可以通过药物干扰多毒力因子调节（MvfR）调控而在体内被破坏，MvfR是QS电路的一个组成部分，控制毒力，正如我们最近发现的那样，抗生素耐受细胞的形成。我们阐明了MvfR调控子激活的机制，并在体内鉴定了几种抑制MvfR转录因子和/或干扰MvfR调控子活性的小化合物。使用这些化合物，我们将通过三个具体目标来验证我们的假设：1)使用生化，质谱和分子遗传学分析来研究候选化合物的作用机制。2)通过构效关系（SAR）研究，改进最有效的QS抑制剂。3)在合适的动物模型上验证sar改良抑制剂减毒铜绿假单胞菌感染的体内效果。QS信号通路是进化保守的，在许多不同的人类病原体的毒力机制调节中发挥核心作用。因此，通过选择性地干扰QS，我们的数据应该产生典型的见解，这将与开发新型抗感染药物普遍相关，这些抗感染药物可以限制细菌病原体中多药耐药和抗生素耐受性的发展，同时保留有益的共生细菌。此外，抗生素耐受机制的研究和抑制可能对阐明这一尚未解决的现象产生重大影响，并使发现针对抗生素耐受细胞的第一个探针化合物成为可能。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

A quorum sensing small volatile molecule promotes antibiotic tolerance in bacteria.

群体感应小挥发性分子可促进细菌的抗生素耐受性。

DOI：
10.1371/journal.pone.0080140
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Que,Yok-Ai;Hazan,Ronen;Strobel,Benjamin;Maura,Damien;He,Jianxin;Kesarwani,Meenu;Panopoulos,Panagiotis;Tsurumi,Amy;Giddey,Marlyse;Wilhelmy,Julie;Mindrinos,MichaelN;Rahme,LaurenceG
通讯作者：
Rahme,LaurenceG

Considerations and caveats in anti-virulence drug development.

DOI：
10.1016/j.mib.2016.06.001
发表时间：
2016-10
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Maura D;Ballok AE;Rahme LG
通讯作者：
Rahme LG

A method for high throughput determination of viable bacteria cell counts in 96-well plates.

高吞吐量测定96孔板中可行细菌计数的一种方法。

DOI：
10.1186/1471-2180-12-259
发表时间：
2012-11-13
期刊：
BMC microbiology
影响因子：
4.2
作者：
Hazan R;Que YA;Maura D;Rahme LG
通讯作者：
Rahme LG

Molecular Insights into Function and Competitive Inhibition of Pseudomonas aeruginosa Multiple Virulence Factor Regulator.

DOI：
10.1128/mbio.02158-17
发表时间：
2018-01-16
期刊：
mBio
影响因子：
6.4
作者：
Kitao T;Lepine F;Babloudi S;Walte F;Steinbacher S;Maskos K;Blaesse M;Negri M;Pucci M;Zahler B;Felici A;Rahme LG
通讯作者：
Rahme LG

Assessing Pseudomonas aeruginosa Persister/antibiotic tolerant cells.