The Twort-like bacteriophages of Staphylococcus aureus: paradigm phages for novel therapeutics

 描述（由申请人提供）：在20世纪40年代引入抗生素后不久，开始出现对这些药物具有抗性的细菌菌株。今天，对多种广泛类别的抗生素具有耐药性的细菌菌株的持续出现引起了普通医学界的严重关注，一些人甚至认为我们可能即将进入“后抗生素时代”。在耐药菌中，耐甲氧西林金黄色葡萄球菌（MRSA）是一种主要关注的病原体。噬菌体，感染细菌的病毒，已被提议作为用于治疗人类和动物中的细菌感染的生物控制剂。抗S.金黄色葡萄球菌和MRSA的分离是由于它们对单一类型的大肠杆菌（称为“Twort-like”组）的广泛易感性而促进的。虽然有相当大的兴趣，在使用的治疗，一个重要的，但目前欠发达的研究领域是生物学本身的肿瘤。该提案分为两个主要目标：第一个是研究Twort样噬菌体K的遗传学和生物学，第二个是利用这项研究开发可用于工程或进一步研究这种噬菌体生物学的方法。在第一个目标中，将产生可抑制突变体库，提供该噬菌体中大多数必需基因的图谱，并允许将功能分配给许多未知基因。该项目的第二个目的是开发新的方法，用于基因操作的噬菌体，主要是通过开发一个可用于噬菌体遗传背景的选择标记系统。该系统将允许噬菌体基因被灭活或随意替换，从而允许进行许多未来的基础研究。这里开发的策略也应该在其他噬菌体系统中有用，从而催化整个噬菌体生物学领域的进展。

 DESCRIPTION (provided by applicant): Shortly after the introduction of antibiotics in the 1940's, strains of bacteria that were resistant to these drugs began to emerge. Today, the continued emergence of bacterial strains that are resistant to multiple broad classes of antibiotics has raised significant concern among the general medical community, some even suggesting we may be about to enter a "post-antibiotic era". Among resistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA) is an agent of major concern. Bacteriophages, viruses that infect bacteria, have been proposed as biological control agents for the treatment of bacterial infections in humans and animals. Phage therapy against S. aureus and MRSA is facilitated by their broad susceptibility to a single type of phages, referred to as the "Twort-like" group. While there is considerable interest in the use of phages as therapeutics, an important but currently underdeveloped field of research is the biology of the phages themselves. This proposal is divided into two major aims: the first is to study the genetics and biology of the Twort-like phage K, and the second is to leverage this study to develop methods that can be used to engineer or further study the biology of this phage. In the first aim, the library of suppressible mutants will be generated, providing a map of most of the essential genes in this phage and allowing functions to be assigned to a number of unknown genes. The second aim of the project is to develop new methods for genetic manipulation of phages, primarily by developing a selectable marker system that can be used in the phage genetic context. This system will allow phage genes to be inactivated or replaced at will, allowing a number of future fundamental studies to be conducted. The strategies developed here should also be useful in other phage systems, thus catalyzing progress in the field of phage biology as a whole.