Gonococci: Genetics of Resistance to PMN Proteins

淋球菌：PMN 蛋白抗性遗传学

• 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
• 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

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

淋病奈瑟菌是一种严格的人类病原体，在全球范围内导致超过1亿例淋病病例。 性病淋病的发病率如果没有有效的疫苗抗生素治疗 仍然是减少或阻断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性决定簇的获得， 淋球菌已经对相对便宜的抗生素产生了耐药性;这种耐药性现在需要 使用更昂贵的抗生素，而这些抗生素在贫穷国家并不总是可用的。多药外排泵 淋球菌所具有的抗体对淋球菌抵抗抗生素的能力具有重要作用， 先天宿主防御系统的抗菌剂。特别是，我们的工作表明，地铁-地铁D- MtrE外排泵参与淋球菌对青霉素和大环内酯类的耐药性。该外排泵还 识别宿主抗微生物剂，如抗微生物肽和孕酮。我们已经证明， 在实验性感染的雌性小鼠中，淋球菌引起持续感染需要泵， 体内适应性的程度与控制mtrCDE基因表达的转录调节因子有关。的 DNA结合蛋白在调节淋球菌对抗生素耐药性中的重要性是本研究的主题。 R37 MERIT延期请求。在具体目标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， 可以控制MTR基因座外的许多基因的表达。我们将评估 这种对淋球菌抵抗抗微生物剂的能力的调节以及在实验中的感染过程中， 感染的老鼠在具体目标2中，我们将定义不同的药物的使用、调节和生物学重要性。 用于mtrCDE操纵子转录的启动子。在具体目标3中，我们将定义机制， 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剂的敏感性。从拟议的工作结果将提前 我们关于淋球菌和其他人类细菌病原体如何使用药物外排泵的知识， 转录调节系统，以抵抗经典抗生素以及先天免疫介质