The role of the dynamin membrane-remodelling proteins in developmentally controlled cell division in Streptomyces

链霉菌是无害的土壤细菌，类似于霉菌，因为它们是丝状的，而不是单细胞生物。它们对人类福祉至关重要，因为它们是医生用于治疗传染病的绝大多数抗生素的来源，也为我们提供了许多其他药物，例如用于治疗癌症和帮助器官移植患者。链霉菌通过将称为“气生菌丝”的特殊生殖细丝分裂成长链孢子来繁殖自己，这一过程称为“形态分化”。抗生素的产生与形态分化密切相关。形成休眠孢子的形态分化需要每个气生菌丝同步地铺设50个或更多个规则间隔的特化壁，称为“孢子形成隔”。这些孢子形成隔膜从气生菌丝的侧面向内生长，菌丝的膜内陷在向内生长的壁周围，直到膜和壁在中间融合。我们已经发现了两种被称为“发动蛋白”的蛋白质，它们是这种大规模细胞分裂事件正常发生所必需的。动力蛋白参与了细胞膜的重塑，因为它们内陷和融合，但不知何故，它们也需要稳定合成向内生长的细胞壁的分子机制。这项资助申请的目的是发现发动蛋白如何在分子水平上实现这些功能。我们还知道，发动蛋白存在于与之密切相关的（但实验上非常困难的）细菌结核分枝杆菌中，结核分枝杆菌导致致命的结核病，我们将在链霉菌中研究的细胞分裂机制与这种杀手细菌的细胞分裂机制密切相关。因此，这项工作也可能为另一种对人类健康很重要的细菌的细胞分裂机制提供重要的见解。找到抑制病原菌细胞分裂的方法可能会为它们引起的疾病提供更有效的治疗方法。

Streptomyces are harmless soil bacteria that resemble moulds in that they are filamentous, rather than unicellular organisms. They are vital to human welfare because they are the source of the vast majority of antibiotics used by doctors to cure infectious diseases, as well as providing us with numerous other medicines used, for example, to treat cancer, and to help organ transplant patients. Streptomyces reproduce themselves by dividing specialised reproductive filaments called 'aerial hyphae' into long chains of spores, in a process called 'morphological differentiation'. Antibiotic production is tightly coordinated with morphological differentiation. Morphological differentiation to form dormant spores requires each aerial hypha to synchronously lay down 50 or more regularly spaced, specialized walls called 'sporulation septa'. These sporulation septa grow in from the sides of the aerial hyphae, with the membrane of the hyphae invaginating around the ingrowing wall, until both membrane and wall fuse in the middle. We have discovered two proteins called 'dynamins' that are required for this massive cell division event to take place normally. The dynamin proteins are involved in remodeling the membranes as they invaginate and fuse, but somehow they are also required to stabilize the molecular machinery that synthesizes the ingrowing cell wall. The aim of this grant application is to discover how the dynamins achieve these functions at the molecular level. We also know that the dynamins are present in the closely related (but experimentally very difficult) bacterium Mycobacterium tuberculosis, which causes the fatal disease tuberculosis, and that the cell division machinery we will be studying in Streptomyces is closely related to the cell division machinery in this killer bug. Thus, this work may also provide significant insights into the cell division machinery of another bacterium important to human health. Finding ways to inhibit cell division in pathogenic bacteria could lead to more effective treatments for the diseases they cause.