Active Infection & Immunity Cells, Biochemistry & Physiology

Investigating the PTSNtr in Pseudomonas aeruginosa

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

The bacterium *Pseudomonas aeruginosa* switches into a dormant, slow-growing state during infection, making it stubbornly resistant to antibiotics. This project targets a three-protein signalling system called PTSNtr that controls the bacterium’s behaviour in that dormant state. Current antibiotics mostly kill actively growing bacteria, so infections caused by dormant *P. aeruginosa*—common in cystic fibrosis patients and chronic wounds—are notoriously difficult to treat. The PTSNtr system is poorly understood, and no existing drugs target it. The researcher will first identify which proteins interact with the system’s key component, PtsN, then build bacterial strains missing parts of the system to see how signalling changes under infection-like conditions, such as nutrient scarcity and immune cell attack. Finally, they will screen compound libraries for drugs that disrupt PTSNtr signalling, aiming to make dormant bacteria vulnerable to existing antibiotics. If successful, this work could reveal a new way to sensitise *P. aeruginosa* to antibiotics without developing entirely new drugs. Because the PTSNtr system is widespread among bacteria, understanding its fundamental biology might also inform strategies against other hard-to-treat infections. The project is primarily curiosity-driven fundamental science, but its focus on disrupting a specific signalling pathway has clear translational potential.

View original technical description
During infection, bacteria are often in a dormant state, where they are less active and are resilient to stresses, including antibiotic treatment. The nitrogen-related phosphotransferase system (PTSNtr) helps control the cell during dormancy. In Pseudomonas aeruginosa, it consists of three proteins that transfer a modifying phosphate from one to the next: PtsP, PtsO, and PtsN. Phosphorylation of PtsN changes its interactions with binding partners. A prior pulldown identified some interactors of PtsN. I will confirm the key interactors and use a proximal labelling method to identify transient interactions. PtsO/PtsP are theorised to be influenced by metabolic signals, recognising the cell status and altering PtsN activity. I will construct bacterial strains lacking PTSNtr components and measure changes in the level of phosphorylated PtsN and the interactions between PtsN and its partners identified in the first part of the project. I will investigate how conditions relevant to P.aeruginosa infections alter PTSNtr signalling, including nutrient-limiting media and macrophage presence. I will attempt to disrupt PTSNtr signalling to sensitise P.aeruginosa to antibiotics, identifying combinations of antibiotics using compound libraries. The PTSNtr has wide- ranging effects but remains poorly understood and studying it may enhance our understanding of how slow growing bacteria regulate different activities.

View the original record at the funder ↗

Researchers

Peter McBride (EPMC Awardee)

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Original classification

PhD Studentship (Basic)

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