Illuminating the dark matter of bacteriophages that kill antibiotic-tolerant bacteria

• Applicant: Dr. Tom Luthe
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550235679

Viruses of bacteria, known as bacteriophages or phages, are found ubiquitously on planet earth, are major drivers of evolution, and are shaping bacterial communities. Research on bacteriophages and their interactions with the host has contributed drastically to the understanding of the molecular basis of life in general and to the development of molecular tools used routinely in the lab. Additionally, these viruses can also be used to treat bacterial infections, a concept called phage therapy, which is currently re-emerging as a potential solution for tackling the uprising problem of multidrug-resistant pathogens. Especially associated with chronic infections, bacteria can persist in a dormant, metabolically inactive and non-growing state, which interferes with the bactericidal effect expressed by most antibiotics. Like other viruses, bacteriophages depend on a susceptible and metabolically active host cell to replicate and release progeny in a productive infection. While most phages fail to replicate on dormant cells, recently two phages able to infect dormant, antibiotic-tolerant Peudomonas aeruginosa were isolated by the group of Prof. Alexander Harms. Both phages, Paride and Ercole, are unrelated but share a dependence on the same bacterial stress responses that also drive the antibiotic tolerance of these cells. However, the exact mechanism is not yet investigated. In comparison to Paride, Ercole has a significantly smaller genome size and allows for a direct genetic approach, targeting single genes for unraveling the underlying mechanism of dormant phage replication. The main goal of this research project is to identify genes used by phage Ercole to infect dormant, antibiotic-tolerant bacteria as well as their host targets to determine the overall infection strategy. Additionally, the results will be used for systematic and comprehensive bioinformatics analyses of the known phage diversity to illuminate the distribution and relevance of this ability in nature and if this ability can be transferred to other phages. Understanding the process of infecting dormant cells will be a major breakthrough by teaching us long-evolved viral strategies to overcome resilient bacteria. Therefore, this project will result in new ecological insights and possible clinical applications for hard to treat infections with dormant, antibiotic-tolerant bacteria.

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Dr. Alexander Harms