A new method lets researchers pluck genes from viruses that kill bacteria without first having to grow the bacteria in a lab. This matters because most bacteriophages—the most abundant lifeforms on Earth—remain unknown. Current techniques can only study phages that infect 30 bacterial types, and 70–95% of genes in known phage genomes have no identifiable function. That unexplored genetic territory likely contains many antibacterial compounds, which are urgently needed as antibiotic resistance grows. The researcher has already used this method to find a misannotated viral enzyme that recycles bacterial nucleotides and a novel viral phospholipase with a lipid-remodelling function. Now they will apply it to hunt for anti-biofilm genes active against *Pseudomonas aeruginosa*, a pathogen that plagues people with cystic fibrosis. If successful, the work could yield new tools to break down bacterial biofilms—slimy coatings that make infections stubbornly resistant to treatment. This is fundamental science: it will illuminate viral “dark matter” and provide a blueprint for similar screens in other systems. Past discoveries of cryptic viral genes have led to gene-editing tools and novel enzymes; this project could open a similar door.
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Antimicrobial resistance (AMR) is one of the largest health crises humanity is facing in the 21st century, with the number of annual deaths projected to eclipse any other death cause by 2050. Bacteriophages (viruses that kill bacteria) represent an exciting and valuable research area, because they offer a promising alternative to antibiotics. However, in spite of being the most numerous biological entity on the planet, the vast majority of bacteriophages are completely unknown to us, due to the fact that current research methods enable us to investigate bacteriophages infecting only 30 bacterial genera. Moreover, most predicted genes (70-95%) in isolated bacteriophage genomes are of an unknown function and are dissimilar to any currently known genes, presenting a vast, unexplored territory with novel metabolic, therapeutic, and biotechnological applications. Since bacteriophages kill bacteria, a lot of these cryptic genes have antibacterial activities that can greatly improve our arsenal of weapons against antibiotic-resistant pathogens. As a phage researcher with demonstrable experience in characterisation of cryptic viral genes, I have developed and tested a high-throughput method to decipher the role of unknown phage genes. This method represents a significant upgrade on currently available phage research methods because it avoids the need to isolate and culture the bacterial host before isolating the specific phage that infects it. Instead, it can identify viral genes with antimicrobial activity, providing direct pipeline from environmental or clinical samples to utilisation of viral products in our fight against AMR pathogens. Using this method, I have already identified and characterised a previously misannotated viral enzyme responsible for recycling of bacterial nucleotides and assigned a lipid-remodelling function to a novel viral phospholipase, dissimilar to previously known bacterial or viral enzymes of similar function. In this proposal I will use this method to identify and test novel viral products with anti-biofilm activity against cystic fibrosis-relevant bacterial pathogen Pseudomonas aeruginosa. I will accomplish this through three work Aims in which: I will create viral metagenomic libraries from from several clinical, industrial and environmental sources. I will identify novel viral genes with anti-biofilm activities by performing high-throughput screening of my viral metagenomic libraries. I will characterise identified viral gene products via molecular, biochemical and bioinformatic methods, and test their anti-biofilm activity in several respiratory disease lab models. The fundamental scientific outcomes of this project will shine a light on the bacterial and viral “dark matter” – cryptic genes without any similarity to previously known genes in our databases. Understanding the role of these genes will also enable me to characterise new bacteriophages in the future and thus empower the whole of biomedical scientific community, by providing tools for identifying potential therapeutic bacteriophages essential in our battle against drug-resistant bacterial infections. Additionally, the work described here will serve as a blueprint for performing similar functional metagenomic screens of cryptic viral genes in a variety of different systems, forming a solid basis for a promising, independent research career.
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