Initiation of endospore formation in clostridia

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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.