Polyamine Modulation of Goncoccal Virulence

描述（由申请人提供）：淋病奈瑟菌是一种严格意义上的人类病原体，每年在全球范围内导致约9500万例淋病病例。在没有有效疫苗的情况下，抗生素治疗仍然是减少或阻断淋球菌在社区传播的主要机制。不幸的是，由于突变的发展或耐药决定因素的获得，淋球菌已经对相对便宜的抗生素产生了耐药性，需要新的策略来应对这一问题。淋病是人类的一种古老疾病。因此，这种严格的人类病原体已经进化出应对抗菌素威胁的机制也就不足为奇了。我们已经确定了淋球菌使用的一种新机制来抵抗宿主来源的抗菌剂（例如，先天宿主防御介质），这些抗菌剂模仿经典抗生素的作用；这种抗性涉及淋球菌被宿主衍生的多胺覆盖。我们发现生物相关浓度的多胺也可以抑制淋球菌的生物膜形成。使用精胺作为模型多胺，我们已经获得了淋球菌在其存在下产生应激反应的证据。为了更好地了解多胺在感染过程中如何影响淋球菌的致病潜力，我们将定义在确定多胺介导的生物膜形成和分散调节以及淋球菌与宿主细胞相互作用中重要的细菌因子（Specific Aim 1）。我们还将确定淋球菌在生理相关精胺水平存在时在转录和翻译水平上的反应，并将构建精胺应答基因的非极性突变，以便更好地了解这种病原体如何在感染期间利用宿主多胺进行增殖（Specific Aim 2）。在为期两年的资助期间获得的结果应该提供关于淋球菌如何在其自然环境中对化合物作出反应的新见解，这对于开发新的治疗药物来阻断感染或根除男性和女性生殖器粘膜表面的淋球菌是重要的。

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae is a strict human pathogen that causes an estimated ninety-five million cases of gonorrhea worldwide 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 and new strategies will be needed to counteract this problem. Gonorrhea is an ancient disease of mankind. Thus, it is not surprising that this strict human pathogen has evolved mechanisms to deal with antimicrobial threats. We have identified a novel mechanism used by gonococci to resist the host-derived antimicrobials (e.g., mediators of innate host defense) that mimic the action of classical antibiotics; this resistance involves the coating of gonococci with host-derived polyamines. We have found that biologically relevant concentrations of polyamines can also inhibit biofilm formation by gonococci. Using spermine as a model polyamine, we have acquired evidence that gonococci mount a stress response in its presence. In order to better understand how polyamines influence the pathogenic potential of gonococci during infection, we will define bacterial factors that are important in determining polyamine-mediated modulation of biofilm formation and dispersion, as well as the interaction of gonococci with host cells (Specific Aim 1). We will also determine the responses made by gonococci at the transcriptional and translational levels in the presence of physiologically relevant levels of spermine and will construct nonpolar mutations in spermine-responsive genes so as to better understand how this pathogen might use host polyamines to proliferate during infection (Specific Aim 2). The results obtained during the two-year funding should provide novel insights regarding how the gonococcus responds to compounds in its natural environment, which is important in the development of new therapeutic agents that block infection or eradicate gonococci at the genital mucosal surface of men and women.