Mechanism of spore germination

描述（由申请人提供）：对于芽孢杆菌和梭菌属引起的严重感染，传染源通常是孢子而不是营养芽杆菌，代表控制传染周期的干预点。发芽是许多感染的基本早期事件，包括：炭疽（B。anthracis）、C.艰难梭菌相关感染（CDI）、伤口和胃肠道感染、气性坏疽、破伤风、肉毒杆菌中毒和其他严重疾病。孢子进入人体后很快就萌发，或者在实际萌发和发病前在体内长时间休眠。孢子是哈代，不容易通过自然方式从体内清除，并且对抗生素不敏感。它们强健的物理性质需要长时间的抗生素治疗，具有发展严重药物不耐受的高风险，并且在许多情况下（例如，CDI和炭疽），残留的孢子会在停止初始治疗后引起再次感染。我们假设，在暴露后阻断或延迟发芽将有助于减缓生长周期，并在多药耐药性的情况下提供另一条防线。还希望能够诱导萌发，使细菌易受在较短治疗时间表上提供的传统抗生素的影响。炭疽孢子萌发的研究进展现在已经达到了直接检查萌发过程和机制的水平，并开发出真实的对策。使用B。炭疽作为模型系统，该建议使用验证的，跨物种保守的，细菌孢子萌发所需的基因，以确定膜拓扑结构，蛋白质相互作用，复合物的形成和负责这一过程的蛋白质的分子机制。这些研究将为未来的翻译工作提供坚实的基础，以控制发芽作为医学对策的一种手段。 公共卫生相关性：孢子形成细菌在生物防御中受到极大关注[例如，炭疽]和新出现的感染[例如，CDI]。详细了解孢子萌发的机理将确定未来小分子化合物控制的分子靶点，从而预防或增强萌发的启动，导致细菌形式更容易受到医学对策的影响。

DESCRIPTION (provided by applicant): For serious infections caused by Bacillus and Clostridia species the contagion is often the spore not the vegetative bacillus and represents an intervention point for controlling the infectious cycle. Germination is an essential early event for numerous infections including: anthrax (B. anthracis), C. difficile- associated infections (CDI), wound and GI infections, gas gangrene, tetanus, forms of botulism and other serious diseases. Germination can be rapid, occurring soon after spores enter the body, or can linger dormant for extended periods in the body before actual germination and onset of disease. Spores are hardy, not easily cleared from the body by natural means and are not susceptible to antibiotics. Their robust physical properties necessitate prolonged periods of antibiotic treatment with a high risk of developing serious drug intolerances and, in many instances (e.g., CDI and anthrax), residual spores cause re-infections after initial treatments are stopped. We hypothesize that blocking or delaying germination after exposure will be useful to slow the growth cycle and provide another line of defense in the instance of multi-drug resistance. It is also desirable to be able to induce germination, rendering the bacterium vulnerable to traditional antibiotics provided on a shorter treatment schedule. Research progress in anthrax spore germination are now to the level required to directly examine the germination processes and machineries, and develop means for real countermeasures. Using B. anthracis as the model system, this proposal uses validated, cross-species-conserved, genes required for bacterial spore germination to determine membrane topologies, protein interactions, complex formation and molecular mechanisms of the proteins responsible for this process. These studies will provide a solid basis for future translational work towards the goal of controlling germination as a means of medical countermeasures. PUBLIC HEALTH RELEVANCE: Spore-forming bacteria are of great concern in biodefense [e.g., anthrax] and emerging infections [e.g., CDI]. Detailed mechanistic understanding of spore germination will identify molecular targets for future small compound control, allowing either prevention or enhanced initiation of germination that result in bacterial forms far more susceptible to medical countermeasures.