Initiation of endospore formation in clostridia

有些细菌能够在自然界中产生深度休眠和高度抗性的孢子，使其难以从医院环境、食品和药物制剂中根除。形成孢子的能力由细菌家族芽孢杆菌属和梭菌属的成员共享。前者需要空气生长，而后者只能在没有氧气的情况下生长，被称为厌氧菌。许多梭菌物种已经声名狼借，因为它们导致人类疾病，主要是由于孢子的产生。例如，艰难梭菌对许多抗生素具有高度耐药性，并在我们的医院中造成严重问题，有时导致死亡。一旦感染在医院病房爆发，孢子的存在使其很难控制。病房经常需要关闭进行严格消毒。同样，肉毒梭菌的孢子仍然是食品防腐工业中的一个潜在的严重问题，因为它们能够承受高温和高压。此外，9/11事件后，公众对孢子形成生物的关注加剧，因为它们构成了潜在的生物恐怖主义威胁。巧合的是，梭菌形成孢子的能力可能是它对人类最大的潜在好处。孢子可以作为治疗癌症的药物输送系统。当注射到血液中时，梭菌孢子无法发芽和生长，因为正常健康的组织含有氧气。然而，实体瘤的中心块缺乏氧气，进入肿瘤的孢子能够在那里发芽。然后它们增殖并建立一个活跃生长的细菌群体，特别限于肿瘤块。这种独特的功能提供了机会，提供治疗剂选择性地实体肿瘤，简单地赋予生物体的基因能够直接生产抗癌药物。经过充分研究的模式生物枯草芽孢杆菌含有一组相互作用的蛋白质分子（称为磷继电器），负责感知环境变化，作为启动孢子发育过程的前奏。据推测，所有的孢子形成者都拥有类似的磷酸继电器。最近，已经确定了许多梭菌家族成员染色体的整个DNA序列。令我们惊讶的是，它们不制造磷酸化蛋白质。梭状芽孢杆菌被认为类似于在我们的大气层含有氧气之前存在于地球上的更原始的生命形式。关于可能标志着这一重要生物群孢子形成开始的环境变化知之甚少，本研究项目的目的是发现在没有磷继电器的情况下触发孢子形成的因素。如果我们能解开这个谜团，那么科学家们就有可能设计出干扰梭菌孢子形成的策略。这将为预防孢子形成和降低C.食物中的肉毒杆菌孢子和C.在医院病房里很困难。它还将导致更有效地生产用于抗癌疗法的孢子制剂。与BB/D522797/1联合。

Some bacteria are capable of producing profoundly dormant and highly resistant spores in nature, making them difficult to eradicate from hospital environments, foodstuffs and pharmaceutical preparations. The ability to form spores is shared by members of the bacterial families Bacillus and Clostridium. The former require air for growth, whereas the latter can only grow in the absence of oxygen and are known as anaerobes. A number of Clostridium species have achieved notoriety because they cause human disease, largely as a consequence of spore production. For example, Clostridium difficile is highly resistant to many antibiotics and causes serious problems in our hospitals, sometimes leading to mortality. Once an infection breaks out in a hospital ward the presence of spores make it very difficult to control. Wards frequently have to be closed for rigorous disinfection. Similarly, the spores of Clostridium botulinum remain a potentially serious problem in the food preservation industry because they are able to withstand high temperatures and pressures. Moreover, public concern about spore-forming organisms have been heightened post 9/11, as they pose a potential bioterrorism threat. Paradoxically, it is the ability to form spores that presents Clostridium with, perhaps, its greatest potential benefit to mankind. Spores can be exploited as a drug delivery system for treating cancer. When injected into the bloodstream, Clostridium spores are unable to germinate and grow because normal healthy tissues contain oxygen. However, the central mass of solid tumors is devoid of oxygen and those spores that enter a tumour are able to germinate there. They then proliferate and establish an actively growing bacterial population, specifically restricted to the tumour mass. This unique feature provides the opportunity to deliver therapeutic agents selectively to solid tumours, simply by endowing the organism with genes able to direct the production of anticancer drugs. The well-studied model organism, Bacillus subtilis, contains a group of interacting protein molecules (called a phosphorelay) responsible for sensing environmental changes as a prelude to launching the process of spore development. It was assumed that all spore-formers would possess a similar phosphorelay. Recently, the entire DNA sequence of the chromosomes of a number of Clostridium family members have been determined. To our surprise, they do not make phosphorelay proteins. The clostridia are believed to resemble the more primitive life forms that were present on Earth before our atmosphere contained oxygen. Little is known about the environmental changes that might signal the onset of spore formation in this important group of organisms and the objective of this research project, is to discover what triggers sporulation in the absence of a phosphorelay. Should we solve this riddle, then scientists may be able to devise strategies that interfere with spore formation by clostridia. This will open up new ways of preventing spore formation and reducing the incidence of C. botulinum spores in foods and the spore load of C. difficile in hospital wards. It should also result in the more effective production of spore preparations for use in anticancer therapies. Joint with BB/D522797/1.