Thioredoxin mediated Acinetobacter baumannii colonization in the GI tract

硫氧还蛋白介导的鲍曼不动杆菌在胃肠道中的定植

基本信息

批准号：
9092838
负责人：
Bernard Pragash Arulanandam
金额：
$ 18.38万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9092838
关键词：
Acinetobacter Acinetobacter Infections Acinetobacter baumannii Address Adopted Animals Antibiotic Resistance Antibiotics Antibodies Antigen-Antibody Complex Applications Grants Bacteria Bacterial Attachment Site Bacterial Infections Biological Assay Case Study Centers for Disease Control and Prevention (U.S.)Clinical Communities Desiccation Disease Disease Outbreaks Dissociation Drug Targeting Economic Policy Eligibility Determination Environment Enzyme Inhibition Enzymes Epithelial Exhibits Foundations Gastrointestinal tract structure Gene Expression Genes Health Healthcare Helicobacter pylori Homeostasis Homologous Gene Hospitals Human Immune Immune Sera Immunoglobulin A Immunoglobulins Infection Institution Intestines Laboratories Link Literature Malignant Neoplasms Malignant neoplasm of pancreas Mediating Microbial Drug Resistance Middle East Modeling Molecular Monoclonal Antibodies Mucous body substance Multi-Drug Resistance Mus Nosocomial Infections Oral Oral Administration Oxidoreductase Passive Immunization Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Prevalence Process Proteins Reagent Recombinants Reporting Resistance Respiratory Tract Infections Role Secretory Component Secretory Immunoglobulin A Site Sulfhydryl Compounds Surface TXN gene Testing Therapeutic United States Virulence Wound Infection base chemotherapy combat disulfide bond reduction disulfide compound gastrointestinal gastrointestinal infection improved in vitro Assay in vivo inhibitor/antagonist insight intestinal epithelium mortality multi-drug resistant pathogen mutant novel novel strategies pathogen polyclonal antibody prophylactic public health relevance response small molecular inhibitor small molecule therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Acinetobacter baumannii is a major nosocomial and combat related pathogen primarily associated with respiratory and wound infections. Ubiquitous in the environment, this pathogen is highly resistant to desiccation and antibiotics leading many healthcare institutions to adopt strict screening protocols of patients admitted to the hospital to control spread. Despite extensive literature demonstrating its ability to colonize the human GI tract, and at least one study proposing a link between GI tract colonization and acquisition of antibiotic resistance, no empirical studies have been reported to study the mechanism of GI tract colonization. Recently, our laboratory set out to address this shortcoming utilizing a murine oral GI challenge model. To that end, we observed enhanced GI tract colonization and infection in the presence of SIgA, contrary to previous reports suggesting the bacteria proteolytically degraded SIgA to neutralize its protective barrier function. We observed reduction of the disulfide bonds and release of secretory component (SC) from the immunoglobulin. Absence of SIgA resulted in both decreased bacterial attachment and mortality in IgA deficient animals. In vitro assays showed that gene expression of the bacterial enzyme thioredoxin-A (TrxA) was up regulated in response to SIgA exposure. Consequently, inhibition of this enzyme with an asymmetric disulfide compound (PX-12), reported to specifically inhibit thioredoxin and thioredoxin-fold motif (-C-X-X-C-) containing proteins, resulted in decreased bacterial attachment to intestinal epithelial sections obtained from WT mice. Furthermore, deletion of the trxA gene from a MDR A. baumannii clinical isolate (∆trxA) significantly reduced virulence. Based on these observations, we hypothesize that reduction of SIgA by A. baumannii secreted TrxA enhances bacterial colonization, thus immuno- and drug-targeting TrxA provides a novel approach to control of this important MDR pathogen. The proposed study will test this central hypothesis by first delineation of this novel Acinetobacter pathogenic mechanism of TrxA-mediated dissociation of SC from SIgA and enhancement of bacterial attachment, using comparisons of WT MDR clinical isolate with our ∆trxA mutant. The unique pathogenic mechanism will be further assessed/confirmed with inhibition of TrxA function by antibody and small molecule drug treatment. The results of the proposed antibody and drug studies will provide a foundation for the development of therapeutic treatments (e.g. monoclonal antibodies, refined small molecule asymmetric compounds with improved potency) for this important MDR pathogen.

描述（由申请人提供）：鲍曼尼氏菌是主要的医院和战斗的病原体，主要是伴有的，是在环境中采用严格的患者筛查方案。控制传播。口服gi挑战模型。免疫球蛋白的缺失导致iga缺乏的imals均导致皮肤蛋白质蛋白质（TRXA）的基因表现出来不对称的二硫化物化合物（PX-12）。）明显降低了病毒性。 TRXA介导的SC从SIGA中解散的thel acinetobacter致病机制，并使用我们的∆ TRXA机制增强了WT MDR临床分离株的Parison，并通过进一步评估/确认了Ibody和Smolecule药物治疗的进一步评估/确认。对于这种重要的MDR病原体，为发育的综合处理（例如单克隆抗体，精制的小分子不对称化合物具有改善的小分子不对称化合物）的基础。