Exploiting phages and toxin-antitoxin systems for synthetic biology, bacterial pathogen host range analysis, phage therapy and novel antibiotics.

噬菌体是细菌病毒，是地球上最丰富的生物实体。作为细菌捕食者，它们的数量是宿主的10：1，但细菌仍然存在，因为它们进化出了聪明的策略，以避免噬菌体感染的潜在致命影响。这些包括噬菌体受体改变、限制和修饰(R&M)、CRISPR-Cas机制和通用流产感染(Abi)系统，其中一些具有毒素-抗毒素(TA)功能。III型TA系统可以具有Abi能力，这些系统通过RNA抗毒素在相应的细菌宿主中抑制蛋白质内切核酸酶毒素的自杀致命性。在这个项目中，学生将研究噬菌体生物学的多个方面。他/她将使用合成生物学对宿主范围有限的噬菌体进行基因工程，使其进化成可能感染各种细菌病原体的混杂病毒，从而增加它们在开发致命噬菌体治疗模型方面的潜在效用。此外，学生将研究一些噬菌体如何在细菌感染时被噬菌体激活的内源性III型TA系统流产-但仍导致病毒复制的终止(该系统最初可能在细菌中进化以减少其噬菌体寄生虫的繁殖)。病毒从III型系统中逃逸的机制将被研究。最后，学生将筛选不同的小分子文库，以寻找能够激活细菌病原体中内源性致死TA系统的化学实体，作为鉴定新型化疗抗菌剂的新途径。

Bacteriophages (phages) are bacterial viruses that are the most abundant biological entities on Earth. As bacterial predators they outnumber their hosts by 10 to 1 yet bacteria are still around because they have evolved clever strategies to avoid the potentially lethal impacts of phage infection. These include phage receptor alterations, restriction and modification (R&M), CRISPR-Cas mechanisms and generic abortive infection (Abi) systems, some with toxin-antitoxin (TA) functionality. Type III TA systems can have Abi capacity and these operate via an RNA antitoxin that suppresses the suicidal lethality of a proteinaceous endoribonuclease toxin in the corresponding bacterial hosts. In this project the student will investigate multiple aspects of phage biology. He/she will use synthetic biology to genetically engineer phages with restrictive host ranges to evolve them into promiscuous viruses that may be able to infect diverse bacterial pathogens, thereby increasing their potential utility in the development of lethal phage therapy models. Further, the student will investigate how some phages are aborted on bacterial infection by endogenous Type III TA systems that are phage-activated - and yet lead to the termination of viral replication (a system that may have evolved in bacteria originally to diminish propagation of their phage parasites). The mechanism of viral escape from the Type III systems will be investigated. Finally, the student will screen diverse small molecule libraries to search for chemical entities that can activate endogenous lethal TA systems in bacterial pathogens as a new route to the identification of novel chemotherapeutic antimicrobials.