Mechanism of streptococcus virulence regulation by bacterial peptide signals

描述（由申请人提供）：A组链球菌（GAS）是一种导致显著发病率和死亡率的人类特有病原体。鉴于最近GAS侵袭性疾病爆发的增加，GAS中的抗生素耐药性以及缺乏人类疫苗，因此不能忽视识别新的抗菌靶标以改善感染控制的需求。细菌细胞间通讯机制为抗菌药物的发现提供了一个有前途的目标，因为它提供了一种除生长抑制外的感染控制手段。GAS全局转录调节因子RopB控制多种毒力因子的表达，包括分泌型蛋白酶SpeB，其是宿主组织损伤和疾病传播所需的。以前的数据表明，RopB需要生长期特异性的环境信号来介导基因调控。最近，通过在结构生物学，生物物理学，细菌遗传学和细菌发病机理的专业实验室的合作努力，我们证明了RopB是GAS通讯机制的一个组成部分，它使用生长期特异性分泌肽作为细胞间信号来协调毒力基因调控。虽然我们在低细胞密度下将Vfr的分泌信号序列鉴定为RopB抑制信号，但特异于高细胞密度的激活信号的遗传同一性仍然未知。本研究旨在识别和表征肽信号，并评估其对GAS毒力的影响。该提案的目的是加强对GAS中细胞间信号机制的分子理解，长期目标是设计针对细菌通讯的抗感染策略。成功完成拟议的研究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，而且还可能为未来抗感染药物的开发提供支架。

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.