Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens

革兰氏阴性细菌病原体的感染依赖性脆弱性

基本信息

批准号：
10592676
负责人：
Corrella S Detweiler
金额：
$ 50.87万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-07 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592676
关键词：
Affect Animals Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Bacterial Infections Biological Biology Ceftriaxone Cell Culture System Cell Culture Techniques Cell Membrane Permeability Cell physiology Cells Chemicals Clinical Combating Antibiotic Resistant Bacteria Cytolysis Data Disease Generations Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Gram-Positive Bacteria Growth In Vitro Infection Ion Transport Laboratories Lipid Bilayers Macrophage Maintenance Mammalian Cell Membrane Microbial Biofilms Modeling Mus Natural Immunity Pathway interactions Permeability Predisposition Process Production Protons Protoplasts Research Salmonella Salmonella typhimurium Signal Transduction Stress Response Signaling Testing Tissues Toxic effect antimicrobial antimicrobial resistant infection bactericide biological adaptation to stress cell envelope cell injury cell type cellular targeting efflux pump fighting fluidity human pathogen in vivo inhibitor innate immune mechanisms multi-drug resistant pathogen mutant novel strategies pathogen pathogenic bacteria periplasm prevent small molecule tool transcriptome voltage

项目摘要

SUMMARY The larger goal of the project is to identify infection-dependent weaknesses of Gram-negative bacterial pathogens that could be exploited chemically. We focus on the human pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and its survival within mammalian cells and use cell culture infection models and small molecules as tools. We and others have observed that some small molecules that are not effective against Gram-negative bacteria in media prevent pathogen survival during infection of cells and animals. Gram-negative bacteria likely become vulnerable during infection to small molecules because a variety of host innate immune mechanisms permeabilize the bacterial cell envelope and/or occupy efflux pumps, enabling compounds to reach a periplasmic or cellular target. When laboratory media imitates host innate immunity by permeabilizing the outer membrane, these compounds inhibit bacterial growth. We have identified small molecules that under broth conditions that permeabilize the outer membrane or in protoplasts, dissipate bacterial inner membrane voltage without physically disrupting the lipid bilayer. Membrane voltage disruption could compromise bacteria by, for instance, interfering with energy production and/or activating stress- response signaling. The compounds do not disrupt mammalian membranes at concentrations that kill S. Typhimurium in macrophages and at least one of the compounds reduces tissue colonization in mice, demonstrating in vivo potential for this approach. The Specific Aims will interrogate five distinct molecule classes to determine whether targeting the inner membrane should be pursued as a novel approach to fighting Gram-negative bacterial infections.

概括该项目的更大目标是识别革兰氏阴性细菌的感染依赖性弱点可以化学利用的病原体。我们专注于人类病原体沙门氏菌血清鼠伤寒（鼠伤寒沙门氏菌）及其在哺乳动物细胞中的存活，并使用细胞培养感染模型和小分子作为工具。我们和其他人观察到一些无效的小分子针对培养基中的革兰氏阴性细菌可预防细胞和动物感染期间病原体的存活。革兰氏阴性细菌可能在感染小分子期间变得脆弱，因为多种宿主先天免疫机制将细菌细胞信封和/或占用的外排泵渗透化合物达到周质或细胞靶标。当实验室媒体模仿托管先天免疫时透化外膜，这些化合物抑制细菌生长。我们已经确定了很小的在将外膜或原生质体中渗透的肉汤条件下的分子，消散细菌内膜电压，而无需物理破坏脂质双层。膜电压破坏例如，可以通过干扰能量产生和/或激活应力来损害细菌响应信号传导。这些化合物不会以杀死S的浓度破坏哺乳动物膜。巨噬细胞和至少一种化合物中的鼠伤寒可减少小鼠的组织定植，证明这种方法的体内潜力。具体目的将询问五个不同的分子班级来确定是否应将瞄准内膜作为战斗的新方法革兰氏阴性细菌感染。