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

Lead Research Organisation: University of Cambridge
Department Name: Biochemistry

Abstract

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.

Publications

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