Project Details
Projekt
Molecular mechanisms of phage-antibiotic interactions and their interplay with phage defense systems
Subject Area
Microbial Ecology and Applied Microbiology
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 548547420
Bacteriophage-antibiotic combinational treatment is a promising strategy to counter the surge of non-treatable antimicrobial resistant pathogens, and it has been successfully employed in a few critical cases. However, rational design of phage-antibiotic combinations is hindered by the limited knowledge of their underlying mechanisms. The cellular impact of antibiotics and phages alone is highly complex, and often not well understood. This is even more so for phage-antibiotic combinations, which are largely uncharacterized, and might involve molecular mechanisms beyond the regular drug and phage targeted processes. This project deploys an innovative systems biology approach to uncover the molecular underpinnings of phage-antibiotic interactions, and its interplay with the novel phage defense system CBASS. In a pioneer study, we recently discovered that CBASS extensively modulates the activity of well-established antibiotics, such as antifolates and β-lactams, in the absence of phages. Since CBASS shapes both antibiotic activity and phage infection, we hypothesise that it could also interfere with phage-antibiotic interactions. We will systematically evaluate phage-antibiotic interactions between β-lactam or antifolate antibiotics with T2, T4, and T5 phages in Escherichia coli, as well as how these are affected by CBASS. Using a genome-wide knock-out library of non-essential genes, we will map the genetic determinants of the host involved in the response to the single and co-treatments. Moreover, as the molecular basis of the interaction of CBASS with β-lactams is yet unclear, but important to understand phage-β-lactam interactions, we will also pursue mechanistic follow up of CBASS-β-lactams interactions in the absence of phage. Finally, in the spirit of building and sharing a resource with fellow colleagues of the SPP2330, and with the scientific community, we propose to assemble a pathogen-oriented phage collection, covering up to three pathogens with varied phage defense systems. The datasets and resources that we propose to obtain will not only support this project, but also enable future systematic approaches to study how bacterial immune systems shape phage-antibiotic integrations. Our findings will expose molecular drivers of synergy and antagonism in phage-antibiotic interactions, therefore aligning well with the priority program SPP2330’s research area Cellular organisation and regulation of the viral infection cycle. Moreover, our approach to investigate how a novel phage defense system modules phage-antibiotic interactions also blends in very well with the second research area of Novel anti-viral defence systems.
DFG Programme
Priority Programmes
