Gonococci: Genetics of Resistance to PMN Proteins

淋球菌：PMN 蛋白抗性遗传学

基本信息

批准号：
9040074
负责人：
William Maurice Shafer
金额：
$ 40.27万
依托单位：
EMORY UNIVERSITY
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：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040074
关键词：
Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Area Bacterial Drug Resistance Bacterial Genes Bacterial Physiology Bathing Binding Sites Clinical Communities Country Cytochrome c Peroxidase DNA DNA-Binding Proteins Development Disease Drug Efflux Epithelial Cells Female Funding Gene Expression Genes Genetic Transcription Genital system Goals Gonorrhea Human Infection Inflammation Instruction Ion Transport Knowledge Link Macrolide Antibiotics Macrolides Mediator of activation protein Metabolic Pathway Metabolism Modeling Molecular Mus Mutation Natural Immunity Neisseria gonorrhoeae Nucleotides Operon Pathogenesis Penicillin Resistance Point Mutation Positioning Attribute Predisposition Process Progesterone Proliferating Property Proteins Public Health Pump Regulation Resistance Resistance development Role Sexually Transmitted Diseases Site Sodium Structure Surface System Testing Tetracyclines Transcription Repressor/Corepressor Transcriptional Regulation Vaccines Work antimicrobial antimicrobial peptide bacterial resistance base beta-Lactams bile salts drug development efflux pump fitness gene product genetic regulatory protein genetic resistance in vivo insight neutrophil novel pathogen prevent promoter reproductive tract solute transmission process

项目摘要

Neisseria gonorrhoeae is a strict human pathogen that causes greater than 100 million cases worldwide of the sexually transmitted disease gonorrhea each year. Without an effective vaccine, antibiotic therapy remains the principle mechanism to reduce or block the transmission of the gonococcus in the community. Unfortunately, because of the development of mutations or the acquisition of resistance determinants, the gonococcus has developed resistance to relatively inexpensive antibiotics; such resistance now requires the use of more expensive antibiotics that are not always available in poor countries. Multidrug efflux pumps possessed by gonococci have an important role in the ability of gonococci to resist antibiotics and antimicrobials of the innate host defensive system. In particular, our work has shown that the MtrC-MtrD- MtrE efflux pump participates in gonococcal resistance to penicillin and macrolides. This efflux pump also recognizes host antimicrobials, such as antimicrobial peptides and progesterone. We, have shown that the pump is required for gonococci to cause a sustained infection in experimentally-infected female mice and the degree of in vivo fitness is linked to transcriptional regulators that control mtrCDE gene expression. The importance of DNA-binding proteins in regulating gonococcal resistance to antimicrobials is the topic of this R37 MERIT Extension request. In Specific Aim 1 we will define the transcriptional control processes that modulate expression of the mtrR gene, which encodes a repressor of the mirCDE efflux pump operon and can control the expression of numerous genes outside of the mtr locus. We will assess the importance of such regulation in the ability of gonococci to resist antimicrobials and during infection in experimentally infected mice. In Specific Aim 2 we will define the use, regulation and biologic importance of distinct promoters for transcription of the mtrCDE operon. In-Specific Aim 3 we will define the mechanism by which the products of genes controlled by MtrR and other regulatory proteins impact levels of gonococcal susceptibility to antibiotics and host-derived antimicrobials. The results from the proposed work will advance our knowledge regarding how gonococci and other human bacterial pathogens use drug efflux pumps and transcriptional regulatory systems to resist both classical antibiotics as well as mediators of innate immunity

Neisseria Gonorrhoeae是一种严格的人类病原体，在全球范围内导致超过1亿例病例每年性传播疾病的淋病。没有有效的疫苗，抗生素治疗仍然是减少或阻止淋球菌在社区中传播的主要机制。不幸的是，由于突变的发展或抗药决定因素的获取 Gonococcus已经对相对廉价的抗生素产生了抗性。这样的抵抗现在需要使用更昂贵的抗生素，这些抗生素并不总是在贫困国家使用。多药外排泵淋球菌所拥有的先天宿主防御系统的抗菌剂。特别是，我们的工作表明MTRC-MTRD- MTRE外排泵参与对青霉素和大环内酯类药物的淋球菌耐药性。这个外排泵也识别宿主抗菌剂，例如抗菌肽和孕酮。我们已经表明了淋球菌需要泵在实验感染的雌性小鼠和体内适应性程度与控制MTRCDE基因表达的转录调节剂有关。这 DNA结合蛋白在调节淋球菌对抗微生物的耐药性方面的重要性是该主题 R37优异扩展请求。在特定目标1中，我们将定义转录控制过程调节MTRR基因的表达，该基因编码MIRCDE外排泵操纵子的阻遏物和可以控制MTR基因座之外的许多基因的表达。我们将评估这种调节在淋球菌抵抗抗微生物和感染期间的能力中进行了调节。感染的小鼠。在特定目标2中，我们将定义不同的使用，调节和生物学重要性 MTRCDE操纵子转录的启动子。特定目标3我们将定义该机制由MTRR和其他调节蛋白控制的基因产物影响淋球菌的水平对抗生素和宿主衍生的抗菌药物的敏感性。拟议工作的结果将进步我们关于淋球菌和其他人类细菌病原体如何使用药物外泵和转录调节系统可抵抗经典抗生素和先天免疫的介体