Gonococci: Genetics of Resistance to PMN Proteins

淋球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 性传播疾病淋病每年都有。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药性决定因素的获得， 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能买到。多药外排泵 淋球菌所拥有的在淋球菌抵抗抗生素和 天然宿主防御系统的抗菌剂。特别是，我们的工作表明，MtrC-MtrD- MTRE外排泵参与淋球菌对青霉素和大环内酯类抗生素的耐药。这台外排泵还 识别宿主抗菌素，如抗菌肽和黄体酮。我们，已经证明了 淋球菌需要泵才能在实验感染的雌性小鼠中引起持续感染，并且 体内适合度与控制mtrCDE基因表达的转录调控因子有关。这个 DNA结合蛋白在调节淋球菌对抗菌药耐药性中的重要性是这一主题 R37优点延期请求。在特定的目标1中，我们将定义转录调控过程 调节mtrr基因的表达，该基因编码MirCDE外排泵操纵子的阻遏因子和 可以控制MTR基因座以外的许多基因的表达。我们将评估以下方面的重要性 这种对淋球菌抵抗抗菌剂的能力和在实验感染期间的调节 受感染的小鼠。在具体目标2中，我们将定义DISTINCT的用途、调节和生物学重要性 MtrCDE操纵子转录的启动子。在具体目标3中，我们将定义 由mtrr和其他调节蛋白控制的基因产物会影响淋球菌的水平。 对抗生素和宿主衍生抗菌剂的敏感性。拟议工作的成果将会取得进展 我们对淋球菌和其他人类细菌病原体如何使用药物外排泵和 转录调控系统既能抵抗经典的抗生素，也能抵抗天然免疫的介体

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