Project No. 2348

PRIORITY PROJECT

Primary Supervisor

Dr Franklin Nobrega – University of Southampton

Co-Supervisor(s)

Prof Vincent O’Connor – University of Southampton

Dr Matthew Wand – UKHSA (CASE partner)

Summary

Antimicrobial resistance (AMR) is an emerging problem which left unchecked will cause more deaths than cancer by 2050.

Developing new strategies to mitigate this is an important worldwide health priority. An important complication is the emergence of antibiotic-resistant opportunistic pathogens underlying nosocomial infections. Among these, Klebsiella pneumoniae is one of the most pressing concerns, with rapid geographical spread and growing carbapenem resistance. This is the last line antibiotic so such resistance is a real issue for the treatment of a vulnerable patient cohort. Given this background, developing (bacterio)phage-based therapeutic approaches, especially those exploring phage-antibiotic synergies, is an attractive avenue of investigation. Our team is uniquely placed to test the feasibility of this approach to target, mitigate and show selective toxicity on Klebsiella. The UofS group has developed approaches to identify phage species that target antibiotic-resistant Klebsiella. In collaboration with colleagues at UKHSA, they will extend this investigation to score phage or phage-antibiotic combinations that most efficaciously disrupt Klebsiella strains. The approach will allow multiplexing and a comparative approach to inform on the mechanism of phage and phage-antibiotic action. Previous collaborative work from UofS and UKHSA established the genetically-tractable organism C. elegans as an excellent model for Klebsiella pathogenesis. This generates robust measures to profile and differentiate pathogenicity for a range of clinically-relevant Klebsiella strains curated at UKHSA. This will be used to investigate toxicity of phage/phage-antibiotic on a non-target organism to act as a primer for subsequent development in higher organisms. The quantitative assays will allow us to investigate phage mitigation of pathogenesis prior to, and upon Klebsiella colonization. Furthermore, there is an obvious context of trophic interaction between phage, bacteria and bacterial host that needs to be understood. This can be detailed through use of C. elegans mutants that define the molecular determinants of host biology that might be impacted by phage, bacteria or phage-infected bacteria. Overall this project will provide critical training in the key health priority area AMR. Its overall goal aims to define mechanisms and treatment for a key class of antibiotic-resistant infections.