Mechanism of spore germination

描述(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，代表了控制感染循环的干预点。萌发是许多感染的重要早期事件，包括：炭疽(炭疽杆菌)、艰难梭菌相关性感染(CDI)、伤口和胃肠道感染、气性坏疽、破伤风、各种形式的肉毒杆菌中毒和其他严重疾病。萌发可能很快，在孢子进入人体后不久就会发生，或者在实际萌发和发病之前在体内休眠很长一段时间。孢子很耐寒，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，有很高的严重耐药风险，在许多情况下(如CDI和炭疽病)，残留的孢子在最初的治疗停止后会导致再次感染。我们推测，阻断或延迟暴露后的萌发将有助于减缓生长周期，并在出现多药耐药的情况下提供另一道防线。还希望能够诱导发芽，使细菌容易受到较短治疗方案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并开发真正对策的手段所需的水平。以炭疽杆菌为模型系统，该方案使用验证的、跨物种保守的细菌孢子萌发所需的基因来确定负责这一过程的蛋白质的膜拓扑、蛋白质相互作用、复合体的形成和分子机制。这些研究将为今后的翻译工作提供坚实的基础，以实现将控制萌发作为医学对策手段的目标。 公共卫生相关性：芽胞形成细菌在生物防御[例如，炭疽病]和新出现的感染[例如，CDI]方面非常令人担忧。对孢子萌发的详细机制理解将为未来的小型化合物控制确定分子靶标，从而防止或增强萌发的启动，从而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.