Staphylococcus aureus bacteria use a newly discovered trick to force dormant viruses inside them to wake up and spread resistance genes to other bacteria. These viruses, called prophages, normally sit quietly inside bacterial DNA. But a parasitic genetic element known as a PICI can trigger them to activate, hijacking the virus’s machinery to shuttle antibiotic resistance and toxin genes between bacterial cells. This matters because existing research treats each mobile genetic element in isolation, missing how they interact. The project will map the molecular mechanics of this PICI–phage relationship, determine how common it is across bacterial species, and measure its effect on gene transfer and virulence in a clinically relevant model organism. The research is fundamental science with no immediate practical application. Understanding how bacteria cooperate to share resistance genes could, however, eventually inform strategies to disrupt that cooperation—for instance, by designing molecules that block PICI-mediated prophage induction, preventing bacteria from acquiring resistance without killing them directly. Similar fundamental work on bacterial gene transfer underpinned the development of CRISPR gene editing and modern phage therapy.
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Context: Many bacterial pathogens have become resistant to multiple antibiotics, making infections increasingly difficult to treat. This raises serious concerns that routine surgeries, cancer treatments, and organ transplants could again become high-risk due to untreatable bacterial infections. Bacteria can share instructions for antimicrobial resistance (AMR) through a process called horizontal gene transfer (HGT). This is often facilitated by mobile genetic elements (MGEs), such as bacteriophages (phages) - viruses that infect bacteria - and a related group known as phage-inducible chromosomal islands (PICIs). PICIs act as molecular parasites, hijacking phage machinery to spread their own DNA. These elements, often found together in Staphylococcus aureus and other bacteria, are known to facilitate the transfer of AMR genes, toxins, and immune evasion factors, contributing to the spread of disease. Challenge: Although MGEs are individually well studied, how they interact with each other is still poorly understood. Yet, these interactions may profoundly influence the evolution, virulence, and resistance capabilities of bacterial pathogens. A newly discovered interaction - whereby PICIs actively induce prophages - could be a key mechanism driving the spread of AMR and virulence traits. Aims and Objectives: This research will investigate how this newly identified PICI–phage interaction affects bacterial evolution, gene transfer, and disease potential. The project will pursue three major aims: Characterise the molecular basis and conservation of PICI-mediated prophage induction: How do PICIs trigger prophage activation, and how widespread is this mechanism? Define the impact on HGT and bacterial evolution: How does this interaction influence the mobilisation of DNA and the spread of AMR? Determine the impact on virulence and pathogenicity: How do PICI-phage interactions shape the expression of virulence genes and the ability of bacteria to damage host cells? Staphylococcus aureus is used as the model organism because it is genetically tractable, clinically relevant, and a major contributor to AMR infections globally. Potential Applications and Benefits: The project will improve our understanding of fundamental bacterial biology, offering insights applicable to clinical, industrial, and environmental microbiology. It will provide high-level training in advanced molecular microbiology techniques, transcriptomics, and host–pathogen interaction models. While this is a discovery-driven project, the findings could help shape future strategies to limit the spread of AMR. For example, interfering with MGE interactions could prevent bacteria from acquiring resistance or becoming more virulent. In the long term, this could inform the development of new anti-virulence therapies, phage-based treatments, or targeted antimicrobials that disarm bacteria without promoting resistance. This research is strongly aligned with the MRC’s strategic priorities in AMR, infection biology, and bacterial evolution.
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