Mechanisms of the Development and Maintenance of Salmonella Gallbladder Carriage

沙门氏菌胆囊运输的发生和维持机制

基本信息

批准号：
10721397
负责人：
JOHN S GUNN
金额：
$ 1.18万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10721397
关键词：
Affinity Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Bacteria Biological Biological Assay Cessation of life Cholelithiasis Chronic Ciprofloxacin Clinical Trials Communicable Diseases Data Development Disease Dose Drug Kinetics Enteral Enterobacteriaceae Exhibits Fever Future Gallbladder Gastroenteritis Goals Human Immune response In Vitro Individual Infection Intervention Investigation Life Location Maintenance Measures Medical Methods Microbial Biofilms Modeling Molecular Target Monitor Morbidity - disease rate Mus Operative Surgical Procedures Outcome Study Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Play Process Property Research Resistance Role Safety Salmonella Salmonella typhi Salmonella typhimurium Site Solubility Structure-Activity Relationship Systemic disease Therapeutic Intervention Time Treatment Efficacy Typhoid Fever Work acute infection alternative treatment analog bacterial lysate chronic infection detection limit drug discovery effective therapy efficacy evaluation immune clearance in vivo innovation interest mortality mouse model mutant next generation novel novel therapeutics pathogen pharmacologic prevent small molecule small molecule inhibitor transmission process

项目摘要

Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoid fever caused primarily by Salmonella enterica serovar Typhi (S. Typhi), results in a life-threatening systemic disease that is responsible for significant morbidity and mortality annually worldwide. Approximately 5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the site of persistence. S. Typhi is a human- restricted pathogen, therefore asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model (utilizing S. Typhimurium, which causes a typhoid-fever like disease in mice) and in humans, serving as a substrate to which Salmonellae attach and form a protective biofilm. Thus, biofilm formation is a key step in the establishment of carriers. Traditional antibiotic therapies are usually incapable of clearing chronic S. Typhi infections, as the biofilm phenotype renders the bacteria tolerant to the mechanisms of these drugs. Thus, the identification of novel therapeutics capable of targeting S. Typhi biofilms is necessary in order to eliminate chronic carriage and eradicate the disease. Towards this end, our group has identified four small molecules and two antibodies capable of inhibiting and/or disrupting Salmonella biofilms in vitro. We advance two of the small molecules in this proposal, JG-1 and M4, that both inhibit and disrupt biofilms in vitro and reduce GB bacterial numbers in vivo. We hypothesize that the use of these anti-biofilm compounds in conjunction with an antibiotic will more effectively inhibit and disrupt Salmonella biofilms in vivo in our mouse model of chronic carriage when compared to the administration of antibiotic therapy alone. In Aim 1, we will assess the efficacy of these anti-biofilm compounds at preventing and treating chronic infection compared to traditional antibiotics alone by utilizing our established mouse model of typhoidal chronic carriage. We will also measure important pharmacokinetic and tolerability parameters of these compounds. In order to elucidate the mechanisms by which these compounds antagonize Salmonella biofilms, in Aim 2 we will identify the specific bacterial target(s) of each compound by enriching for mutants exhibiting compound resistance and by performing direct pull-downs of targets from bacterial lysates. Structure activity relationships and derivatives with enhanced physiochemical and biological properties will be generated in Aim 3. In summary, we propose an investigation into the safety, efficacy, and mechanisms of novel anti-biofilm compounds to prevent and treat chronic infections by typhoidal Salmonella. To our knowledge this study will be the first attempt (utilizing subject experts in anti-biofilm medicinal chemistry and Salmonella chronic infection) to specifically target Salmonella biofilm formation in vivo as a means of combating chronic carriage.

沙门氏菌是肠杆菌科细菌，可引起人类和动物的一系列疾病，包括肠热（伤寒）热和胃肠炎。伤寒主要由伤寒沙门氏菌引起，是一种危及生命的全身性疾病，每年在全世界造成显着的发病率和死亡率。大约 5% 的伤寒沙门氏菌感染者成为慢性携带者，并以胆囊 (GB) 作为持续存在的部位。伤寒沙门氏菌是一种人类限制性病原体，因此无症状携带者是疾病进一步传播的关键储存库。我们已经证明，胆结石（GS）有助于小鼠模型（利用鼠伤寒沙门氏菌，在小鼠中引起伤寒样疾病）和人类中 GB 携带的发展和维持，作为沙门氏菌附着的基质并形成保护性生物膜。因此，生物膜的形成是载体建立的关键步骤。传统的抗生素疗法通常无法清除慢性伤寒沙门氏菌感染，因为生物膜表型使细菌对这些药物的机制产生耐受。因此，为了消除慢性携带并根除这种疾病，有必要鉴定能够靶向伤寒沙门氏菌生物膜的新型疗法。为此，我们的小组已经确定了四种小分子和两种能够在体外抑制和/或破坏沙门氏菌生物膜的抗体。我们在该提案中提出了两种小分子 JG-1 和 M4，它们既能在体外抑制和破坏生物膜，又能减少体内 GB 细菌的数量。我们假设，与单独使用抗生素治疗相比，在我们的慢性携带小鼠模型中，将这些抗生物膜化合物与抗生素结合使用将更有效地抑制和破坏体内沙门氏菌生物膜。在目标 1 中，我们将利用我们建立的伤寒慢性携带小鼠模型，评估这些抗生物膜化合物与单独使用传统抗生素相比在预防和治疗慢性感染方面的功效。我们还将测量这些化合物的重要药代动力学和耐受性参数。为了阐明这些化合物拮抗沙门氏菌生物膜的机制，在目标 2 中，我们将通过富集表现出化合物抗性的突变体并通过从细菌裂解物中直接下拉靶标来识别每种化合物的特定细菌靶标。目标3将产生具有增强的理化和生物学特性的结构活性关系和衍生物。总之，我们建议对新型抗生物膜化合物预防和治疗伤寒沙门氏菌慢性感染的安全性、有效性和机制进行研究。据我们所知，这项研究将是首次尝试（利用抗生物膜药物化学和沙门氏菌慢性感染方面的学科专家）专门针对体内沙门氏菌生物膜形成作为对抗慢性携带的手段。

项目成果

期刊论文数量（18）

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 a Host-Targeted Compound to Control Typhoid Fever.

DOI：
10.1128/spectrum.00619-22
发表时间：
2022-06-29
期刊：
MICROBIOLOGY SPECTRUM
影响因子：
3.7
作者：
Hoang, Ky V.;Woolard, Katherine;Yang, Ching;Melander, Christian;Gunn, John S.
通讯作者：
Gunn, John S.

Spectrum of activity of Salmonella anti-biofilm compounds: Evaluation of activity against biofilm-forming ESKAPE pathogens.

DOI：
10.1016/j.bioflm.2023.100158
发表时间：
2023-12-15
期刊：
Biofilm
影响因子：
6.8
作者：
通讯作者：

Development of small molecules that work cooperatively with ciprofloxacin to clear salmonella biofilms in a chronic gallbladder carriage model.

DOI：
10.1016/j.ejmech.2022.114203
发表时间：
2022-03-15
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Woolard KJ;Sandala JL;Melander RJ;Gunn JS;Melander C
通讯作者：
Melander C

A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage.

DOI：
10.1371/journal.ppat.1009192
发表时间：
2020-12
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Sandala JL;Eichar BW;Kuo LG;Hahn MM;Basak AK;Huggins WM;Woolard K;Melander C;Gunn JS
通讯作者：
Gunn JS

Pathoadaptive Alteration of Salmonella Biofilm Formation in Response to the Gallbladder Environment.

沙门氏菌生物膜形成响应胆囊环境的病理适应性改变。

DOI：
10.1128/jb.00774-18
发表时间：
2019
期刊：
Journal of bacteriology
影响因子：
3.2
作者：
Neiger,MichaelR;González,JuanF;Gonzalez-Escobedo,Geoffrey;Kuck,Harkness;White,Peter;Gunn,JohnS
通讯作者：
Gunn,JohnS