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，使它们难以从医院环境、食品和药物制剂中根除。形成孢子的能力是杆菌和梭状芽孢杆菌家族成员共有的。前者需要大气来生长（需氧菌），而氧气对后者是有毒的。因此，梭菌只能在缺氧条件下生长，因此被归类为厌氧菌。许多梭状芽孢杆菌已经臭名昭著，因为它们引起人类疾病，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，并且经常必须关闭病房进行严格消毒。同样，肉毒杆菌的孢子在食品保鲜行业仍然是一个潜在的严重问题，因为它们能够承受高温和高压。此外，公众对孢子形成生物的担忧在9、11事件后加剧，因为它们构成了潜在的生物恐怖主义威胁。矛盾的是，正是梭状芽胞杆菌形成孢子的能力，通过利用它们的孢子作为治疗癌症的递送系统，可能给人类带来了最大的潜在好处。当孢子被注射到血液中时，细菌无法生长，因为正常的健康组织含有氧气。然而，实体瘤的中心肿块缺氧。因此，那些进入肿瘤的孢子能够发芽，并导致一个活跃增长的种群的建立，特别是局限于肿瘤肿块。这种独特的特性通过赋予生物体能够指导所需抗癌药物生产的基因，为选择性地向实体肿瘤输送治疗药物提供了机会。被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（称为磷接力），负责感知环境变化，作为启动孢子发育过程的前奏。假定所有孢子形成者都具有类似的磷接力。最近，许多梭状芽孢杆菌家族成员的染色体的全部DNA序列已经被确定。令我们惊讶的是，它们没有磷接力蛋白。梭状芽孢杆菌被认为类似于在我们的大气含有氧气之前存在于地球上的更原始的生命形式。在这一重要的生物群体中，环境变化可能预示着孢子形成的开始，而我们对环境变化知之甚少，本研究项目的目的是发现在缺乏磷接力的情况下，是什么触发了孢子形成。如果我们解决了这个谜题，那么科学家们就可以设计出干扰梭菌孢子形成的策略。这将揭示预防芽孢形成和减少食物中肉毒杆菌孢子的发生率以及医院病房中艰难梭菌的孢子负荷的新方法。它还应该导致更有效的生产用于抗癌治疗的孢子制剂。与BB/D001498/1接头。

Some bacteria are capable of producing profoundly dormant and highly resistant spores in nature, making them difficult to eradicate form hospital environments, foodstuffs and pharmaceutical preparations. The ability to form spores is shared by members of the bacterial families Bacillus and Clostridium. Whereas the former require atmospheric air for growth (aerobes), oxygen is poisonous to the latter. Thus, clostridia can only grow in the absence of oxygen and are therefore classified 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 and frequently, wards 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, through the exploitation of their spores as a delivery system for treating cancer. When spores are injected into the bloodstream, the bacteria are unable to grow because normal healthy tissues contain oxygen. However, the central mass of solid tumors are devoid of oxygen. Those spores that enter a tumour are therefore able to germinate, and bring about the establishment of an actively growing population, specifically restricted to the tumour mass. This unique feature provides the opportunity to deliver therapeutic agents selectively to solid tumours, by endowing the organism used with genes able to direct the production of the desired 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 have 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, in the absence of a phosphorelay, triggers sporulation. Should we solve this riddle, then scientists may be able to devise strategies that interfere with spore formation by clostridia. This will reveal 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/D001498/1.