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Function and regulation of the intrinsic antibiotic resistome of Neisseria gonorrhoeae

淋病奈瑟菌内在抗生素耐药性的功能和调控

基本信息

批准号：
10646403
负责人：
William Maurice Shafer
金额：
$ 46.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646403
关键词：
Acinetobacter baumannii Africa Aminoglycoside resistance Aminoglycosides Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Cationic Peptides Antimicrobial Resistance Azithromycin Bacteria Cefixime Ceftriaxone Cephalosporins Clinical Clinical Trials Communities Country Data Dedications Defect Developed Countries Developing Countries Development Disease Drug Targeting Female Future GC gene Gene Expression Generations Genes Genetic Screening Gentamicins Gonorrhea Gram-Negative Bacteria Gynecologic Health Homeostasis Host Defense Human Incidence Infection Infectious Agent Knowledge Laboratories Medical Membrane Modeling Mucous Membrane Multi-Drug Resistance Mus Mutation Nature Neisseria gonorrhoeae Pharmaceutical Preparations Physiological Predisposition Process Proteins Pseudomonas aeruginosa Recording of previous events Regulation Report (document)Reporting Research Resistance Resistance development Resources Sensory Sepsis Sexually Transmitted Diseases Societies Structure Sulfonamides Surface System Techniques Therapeutic Transcriptional Regulation Treatment Protocols United States Vaccines Woman Work antimicrobial attenuation bacterial resistance cell envelope clinical efficacy clinical practice combat experience human pathogen insight male male health mouse model mutant novel novel therapeutics pathogenic bacteria programs reproductive reproductive tract resistance gene response screening success transcriptome sequencing uptake

项目摘要

Neisseria gonorrhoeae (the gonococcus; [Gc]) causes both localized, uncomplicated infections at mucosal surfaces and more invasive forms of disease that can have severe medical consequences for the reproductive and general health of men and women. In the United States it is estimated that the incidence of gonorrhea is at least 850,000 cases per year while the worldwide incidence in 2012 was reported to be 78 million cases. In addition to the global problems of disease incidence and impact of gonorrhea on human health, Gc strains have developed decreased susceptibility or clinical resistance to front-line antibiotics currently used in dual therapy (e.g., ceftriaxone and azithromycin) in the USA and other developed countries. Our research program is dedicated to understanding the intrinsic systems possessed by Gc that allow it to resist classical antibiotics as well as cationic antimicrobial peptides/proteins (CAMPs) that participate in innate host defense. In the absence of new antibiotics, especially those recognizing unexploited targets, information regarding the development of resistance to existing antibiotics likely to enter clinical practice is critical. For instance, gentamicin has been used extensively in Africa to treat gonorrhea but resistance data from this part of the world is scant. This is unfortunate because gentamicin has been suggested to be an alternative antibiotic for treatment of gonorrhea in developed countries. We have evidence that loss of a sensory two component system (TCS) termed MisR/MisS results in Gc hyper-susceptibility to both gentamicin (as well as other aminoglycosides) and CAMPs, but not other antibiotics. A recent report documented that loss of the MisR/MisS TCS conferred a survival defect on Gc as assessed in a female mouse model of lower genital tract infection. We hypothesize that such attenuation of Gc was due, in part, to a reduced capacity of MisR-negative Gc to regulate genes important for resistance to host-derived CAMPs. The selective sensitivity of MisR-negative Gc to aminoglycosides and CAMPs is consistent with the self-promoted uptake model invoked for how these antimicrobials enter Pseudomonas aeruginosa and traverse the cell envelope. We will now build on the progress made in our initial studies. In Specific Aim 1 we will use genetic screening techniques, an experimental female mouse infection model and analysis of clinical isolates expressing decreased gentamicin susceptibility to further define the repertoire of Gc genes that contribute to intrinsic gentamicin resistance. We hypothesize that the identified genes will encode proteins that participate in cell envelope structure, membrane integrity and membrane homeostasis that work in unison to impact levels of Gc resistance to aminoglycosides and CAMPs. In Specific Aim 2 we will ascertain the responsiveness of Gc to sub-lethal levels of gentamicin and determine the responsible genes. In Specific Aim 3 we will define the physiological consequences of mutations in the identified genes that influence Gc susceptibility to gentamicin. The results from this work will provide basic knowledge as to how human pathogens like Gc control expression of genes involved in intrinsic resistance to antimicrobials.

淋病奈瑟菌（淋球菌；[Gc]）既可引起粘膜表面的局部、无并发症感染，也可引起侵袭性更强的疾病，可对男性和女性的生殖健康和一般健康造成严重的医疗后果。据估计，在美国，每年至少有85万例淋病病例，而据报道，2012年全球淋病发病率为7800万例。除了淋病发病率和淋病对人类健康的影响等全球性问题外，在美国和其他发达国家，Gc菌株对目前用于双重治疗的一线抗生素（如头孢曲松和阿奇霉素）的敏感性下降或临床耐药。我们的研究项目致力于了解Gc所拥有的内在系统，使其能够抵抗经典抗生素以及参与先天宿主防御的阳离子抗菌肽/蛋白（camp）。在缺乏新抗生素，特别是那些识别未开发靶点的抗生素的情况下，有关可能进入临床实践的现有抗生素耐药性发展的信息至关重要。例如，庆大霉素已在非洲广泛用于治疗淋病，但来自世界这一地区的耐药性数据很少。这是不幸的，因为庆大霉素已被建议作为发达国家治疗淋病的替代抗生素。我们有证据表明，被称为MisR/MisS的感觉双组分系统（TCS）的丧失导致Gc对庆大霉素（以及其他氨基糖苷类）和camp超敏感，但对其他抗生素不敏感。最近的一份报告表明，在下生殖道感染的雌性小鼠模型中，MisR/MisS TCS的缺失导致Gc存活缺陷。我们假设Gc的这种衰减部分是由于misr阴性Gc调节宿主源性camp抗性重要基因的能力降低。misr阴性Gc对氨基糖苷和camp的选择性敏感性与这些抗菌剂如何进入铜绿假单胞菌并穿过细胞包膜的自我促进摄取模型一致。我们现在将在初步研究取得的进展的基础上继续努力。在Specific Aim 1中，我们将使用遗传筛选技术、实验性雌性小鼠感染模型和临床分离株庆大霉素敏感性降低的分析，进一步确定导致庆大霉素内在耐药的Gc基因库。我们假设已鉴定的基因将编码参与细胞包膜结构、膜完整性和膜稳态的蛋白质，这些蛋白质协同作用，影响Gc对氨基糖苷和camp的抗性水平。在特异性目标2中，我们将确定Gc对亚致死水平庆大霉素的反应性，并确定相关基因。在特异性目标3中，我们将定义影响Gc对庆大霉素敏感性的已鉴定基因突变的生理后果。这项工作的结果将为人类病原体如Gc如何控制抗微生物药物内在抗性基因的表达提供基础知识。