Mechanism of streptococcus virulence regulation by bacterial peptide signals

描述（由申请人提供）：A群链球菌（GAS）是一种独特的人类病原体，可导致显著的发病率和死亡率。鉴于最近气体侵入性疾病暴发的增加，气体中的抗生素耐药性以及缺乏人类疫苗，确定新的抗微生物靶点以改善感染控制的必要性不容忽视。细菌细胞间通讯机制为抗菌药物的发现提供了一个有希望的目标，因为它提供了一种控制感染而不是生长抑制的手段。GAS全球转录调节因子RopB控制多种毒力因子的表达，包括分泌蛋白酶SpeB，这是宿主组织损伤和疾病传播所必需的。先前的数据表明，RopB需要生长阶段特定的环境信号来介导基因调控。最近，通过与结构生物学、生物物理学、细菌遗传学和细菌发病机制等专业实验室的合作，我们证明了RopB是GAS通信机制的一个组成部分，它使用生长阶段特异性分泌肽作为细胞间信号来协调毒力基因调控。虽然我们确定了低细胞密度下Vfr的分泌信号序列为RopB抑制信号，但高细胞密度下特异性激活信号的遗传特性尚不清楚。本研究计划旨在识别和表征肽信号并评估其对GAS毒力的影响。这一建议的目的是加强对GAS细胞间信号机制的分子理解，并制定针对细菌通信的抗感染策略。该研究的成功完成不仅将提供溶血性链球菌细胞间信号传导的分子和机制细节，而且可能为未来抗感染药物的开发提供潜在的支撑。

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) is an exclusive human pathogen that causes significant morbidity and mortality. Given the recent rise in GAS invasive disease outbreaks, antibiotic resistance in GAS and lack of a human vaccine, the need to identify novel antimicrobial targets to improve infection control cannot be ignored. The bacterial intercellular communication machinery offers a promising target for antibacterial drug discovery as it provides a means of infection control other than growth inhibition. GAS global transcription regulator, RopB, controls the expression of several virulence factors including secreted protease, SpeB, which is required for host tissue damage and disease dissemination. Previous data suggested that RopB requires growth-phase-specific environmental signals to mediate gene regulation. Recently, through the collaborative effort of laboratories with expertise in structural biology, biophysics, bacterial genetics, and bacterial pathogenesis, we demonstrated that RopB is a component of GAS communication machinery and it uses growth phase-specific secreted peptides as intercellular signals to coordinate virulence gene regulation. Although we identified the secretion signal sequence of Vfr as RopB inhibition signal at low cell density, the genetic identity of activation signals specific for high cell density remains unknown. This research proposal is designed to identify and characterize the peptide signals and assess their impact on GAS virulence. The objective of this proposal is to enhance molecular understanding of the intercellular signaling machinery in GAS with the long-term goal of devising anti-infective strategies that target bacterial communication. Successful completion of the proposed study would not only provide the molecular and mechanistic details of the intercellular signaling in ¿-hemolytic streptococci but also could potentially provide the scaffold for the development of future anti-infective drugs.