Mechanism of spore germination

描述（由申请人提供）：对于由芽孢杆菌和梭状芽孢杆菌引起的严重感染，传染病通常是孢子而不是营养芽孢杆菌，代表控制感染周期的干预点。发芽是许多感染必不可少的早期事件，包括：炭疽（炭疽杆菌）、艰难梭菌相关感染（CDI）、伤口和胃肠道感染、气性坏疽、破伤风、各种肉毒杆菌中毒和其他严重疾病。孢子在进入人体后很快萌发，或者在真正萌发和发病前在体内潜伏较长时间。孢子很顽强，不容易通过自然方式从体内清除，对抗生素也不敏感。它们强大的物理特性需要长时间的抗生素治疗，并有发生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），残留的孢子在最初治疗停止后引起再次感染。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，并在多药耐药的情况下提供另一道防线。还希望能够诱导发芽，使细菌在较短的治疗时间内易受传统抗生素的影响。目前对炭疽孢子萌发的研究进展已经达到了直接考察其萌发过程和机理，并制定切实对策的手段的水平。本研究以炭疽芽孢杆菌为模型系统，使用经过验证的、跨物种保守的细菌孢子萌发所需的基因来确定膜拓扑结构、蛋白质相互作用、复合物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转化工作提供坚实的基础，以控制发芽作为医学对策的手段。

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.