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SoCoBio (Universities of Southampton, Kent, Sussex, Portsmouth and NIAB EMR)

Resistance is futile: hijacking bacterial signal transduction pathways to increase antibiotic uptake.

Primary Supervisor: Dr. Seung Seo Lee (University of Southampton)

Secondary Supervisor: Dr. Christopher Mulligan (University of Kent)

Project Summary
Glucose-6-phosphate (G6P) is a crucial nutrient during Staphylococcus aureus infection, and also known to be involved in antimicrobial resistant (AMR) selection. It is thus important to understand metabolism of bacterial G6P in the fight against AMR. Two-component systems (TCSs) are general bacterial signal transduction pathways, composed of a sensor histidine-kinase (HK) and a transcription regulator. Upon sensing external stimuli, the sensor HK self-phosphorylates, and transfers phosphate to the transcription regulator, initiating or blocking gene expression. While activities of HKs and transcription regulators have been relatively well established, how sensor HKs detect external stimuli is poorly understood.
HptRS is a TCS in S. aureus, which controls G6P metabolism. Recently, another protein, HptA, was identified as a sensor of external G6P, which activates the HptRS system. HptRS activation triggers the expression of UhpT, a G6P transporter, leading to uptake of G6P and enhanced uptake of certain antibiotics into the bacterial cytosol. HptRS and HptA combine in S. aureus to form the three-component system, HptARS. HptA is the first external sensing element in any TCS to be discovered, making HptARS an excellent model system to study how sensing elements interact with HK, how this interaction affects downstream activities, and how we can take advantage of this system to fight infection.
In this project, we aim to elucidate the mechanism of HK HptS interaction with the sensing protein HptA upon the binding of the latter to its stimulant G6P. We will establish structure-activity relationships of affinities between G6P, HptA and HptS using various chemical biology, biophysical, molecular biological and microbiological methodologies, which will allow us to identify interaction hotspots in the three-component system. Understanding signal transduction governing this important process will eventually have a profound impact on understanding the rules of life in bacteria, and building up knowledge for fight against antimicrobial resistance.