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Deciphering the interplay between biogenesis and maintenance of the bacterial cell envelope
Secondary Supervisor(s): Professor David Roper
University of Registration: University of Warwick
BBSRC Strategic Research Priority: Understanding the Rules of Life (Microbiology, Structural Biology)
Project Outline
Antimicrobial resistance in Gram-negative bacteria poses a major global health threat as evidenced by these species dominating the world health organisation’s critical list. These bacteria are responsible for a multitude of infections including, pneumonia, urinary tract infections, meningitis, and wound infections. A fundamental mechanism driving resistance in Gram-negative bacteria is the impermeability conferred by their robust cell envelope, which comprises an asymmetric proteolipid outer membrane, a peptidoglycan layer, and a cytoplasmic inner membrane. (Figure 1).
The maintenance of this multi-layered envelope is essential for bacterial viability. Key biological processes, such as gliding motility, antibiotic efflux, lipid secretion, membrane stabilisation, and nutrient import, are facilitated by dynamic multiprotein complexes that bridge these layers. These protein interactions create a critical linkage between the outer and inner membranes, enabling the coordination necessary for cellular function. Despite the importance of these envelope complexes, the molecular details of their assembly and the coordination of their roles remain poorly understood.
The lab is focused on elucidating the assembly and interactions of trans-envelope complexes, with a particular emphasis on understanding how these multiprotein systems synthesise and maintain the envelope structure during bacterial division. This cooperative functionality is crucial for preventing structural defects as cells undergo division. Specifically, this project will investigate how stabilisation of the outer membrane by the Tol-Pal complex1-3 is coordinated with synthesis of the peptidoglycan layer by PG-synthase complexes.4 By addressing this aspect of envelope maintenance, we aim to reveal insights that could inform the development of drugs designed to destabilise the bacterial envelope.
To achieve these goals, we employ a suite of advanced methodologies, including cryo-electron tomography and fluorescence microscopy for cellular studies, complemented by structural, biophysical, and biochemical techniques to uncover the underlying molecular mechanisms. This comprehensive approach allows us to build a detailed understanding of these essential processes.
The Webby lab offers extensive expertise in cryo-electron microscopy and the study of the Tol-Pal system, while the Roper lab provides world-renowned knowledge in peptidoglycan synthesis and structural analysis. Our collaborative and research-driven environment supports students in developing their projects and pursuing their specific interests. Additionally, our lab maintains strong collaborative ties with other leading research institutions, fostering a network of learning and discovery.
This project is ideal for students passionate about microbiology, antibiotic resistance, and biochemistry. Prospective students are encouraged to reach out for further discussion or to explore mini project opportunities (melissa.webby@bioch.ox.ac.uk).