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、 粘液和分子，如蛋白质，糖和其他溶质，其平衡是关键， 宿主的健康。它也是抵御入侵细菌的第一道防线， 不同微生物群的定植。这种微生物群的一些成员，称为致病菌， 引起严重的局部和全身感染。然而，使用抗生素治疗这些 感染是一个经典的第二十二条军规;可能会暂时缓解，但在未来的道路上，非常解决方案 产生了一个更大的原始问题虽然人们可以摆脱环境的影响， 在一个实施例中，当微生物被杀死时，还消除了拮抗致病菌的有益微生物群，同时 产生进一步增加抗性率的选择。此外， 生态系统的平衡进一步使该系统易于被其他病原生物入侵，并且， 从长远来看，会增加感染和炎症的风险。有真实的需要发展 一种没有这些限制的替代抗菌药物。 该项目的总体目标是发现噬菌体，即感染和杀死 细菌，其对复合物中的耐药致病菌具有特异性活性 人体粘膜表面的环境。这些噬菌体应该对它们的细菌有特异性 目标，并已演变的特点，促进加强活动，面对 这些表面所呈现的复杂性。此外，如果病原体扩散 系统地，这些噬菌体应与常规抗生素协同作用，同时 为新抗性的出现创造了一条陡峭的进化之路。使用其中一 世界上最大的治疗药物的集合，并表征它们的增强活性 在人体粘膜仿生学中，这里描述的研究计划为 开发一种新型的粘膜活性抗菌剂，清除有问题的致病菌 同时保持天然微生物群的平衡。

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.