Mechanistic insights into bacteriophage properties required for enhanced therapeutic potential at mucosal surfaces

项目摘要 人体粘膜表面是一个由细菌、病毒、上皮细胞、 粘液，以及蛋白质、糖和其他溶质等分子，它们的平衡对 宿主的健康状况。它也是抵御入侵细菌的第一道防线，也是 由不同的微生物群进行的定居。这个微生物群中的一些成员，被称为病原体， 造成严重的局部和系统感染。然而，使用抗生素来治疗这些 感染是一种典型的第二十二条军规；可能会暂时缓解，但最终会解决问题 生成原始问题的更大版本。然而，人们可能会摆脱环境中的 病原体，同时也消除了对抗病毒菌的有益微生物群 创造一种选择，进一步增加抵抗率。此外，对世界遗产的破坏 生态系统的平衡进一步使该系统容易受到其他病原体的入侵，并且， 从长远来看，会增加感染和发炎的风险。确实有必要发展 另一种没有这些局限性的抗菌药。 这个项目的总体目标是发现噬菌体，即感染和杀死的病毒。 细菌，这种细菌对复合体中的耐药病原体具有特定的活性 人体粘膜表面的环境。这些噬菌体应该是针对它们的细菌的 目标，以及已进化的功能，以促进在面对 由这样的表面呈现的复杂性。此外，如果病原体蔓延 从系统上讲，这些噬菌体应该与常规抗生素协同作用，同时 为新的抗药性的出现创造了一条陡峭的进化道路。使用其中一种 世界上最大的治疗噬菌体集合及其增强活性的特征 在人类粘膜仿生学方面，这里描述的研究计划为 一类新型黏膜活性抗菌药的研制 同时维持本地微生物区系的平衡。

Project Summary The human mucosal surface is a complex ecosystem made of bacteria, viruses, epithelial cells, mucus, and molecules such as proteins, sugars, and other solutes whose balance is key to the health of the host. It is also the first line of defense against invading bacteria, and a site of colonization by diverse microbiota. Some members of this microbiota, termed pathobionts, cause serious local and systemic infections. However, the use of antibiotics to treat these infections is a classic Catch-22; there may temporary relief but down the road the very solution generates a bigger version of the original problem. Whereas one may rid the environment of the pathobiont, one also eliminates the beneficial microbiota that antagonize the pathobiont while creating a selection that further increases rates of resistance. In addition, the destruction of the balance of the ecosystem further predisposes that system to invasion by other pathobionts, and, in the long run, increases the risk of infection and inflammation. There is a real need to develop an alternative line of antibacterials that lack these limitations. The overall objective of this project is to discover bacteriophage, viruses that infect and kill bacteria, that are specifically active against drug-resistant pathobionts in the complex environment of a human mucosal surface. These phage should be specific for their bacterial target, as well as have evolved features that promote enhanced activity in the face of the complexity presented by such surfaces. Furthermore, should the pathobiont spread systemically, these phage should synergize with conventional antibiotics while simultaneously generating a steep evolutionary path for the emergence of new resistance. Using one of the world’s largest collections of therapeutic phages and characterizing them for enhanced activity in human mucosal biomimetics, the research program described here lays the foundation for the development of a novel class of mucosal-active antibacterials that clear problematic pathobionts while simultaneously maintaining balance of the native microbiota.