Antimicrobial resistance (AMR) is one of the most significant global health challenges, contributing to millions of deaths worldwide and threatening the effectiveness of modern medicine. Klebsiella pneumoniae is a critical-priority pathogen and a leading cause of AMR-related mortality. β-lactam antibiotics remain the most widely prescribed antibiotics globally, but increasing resistance, driven by β-lactamases and other mechanisms, undermines their clinical utility.

The Tooke lab aims to improve our understanding of how β-lactam antibiotics interact with their molecular targets, Penicillin Binding Proteins (PBPs), and how resistance enzymes (β-lactamases) counteract these therapies. By combining structural biology, biochemistry, microbiology and computational approaches, the project will generate new insights to guide future antimicrobial discovery and optimisation.

Our Approach

The project investigates the molecular mechanisms underlying β-lactam activity and resistance in Klebsiella pneumoniae. Using complementary experimental and computational methods, the research will characterise PBPs and β-lactamases, determine how antibiotics and inhibitors bind to these proteins, and identify factors that influence efficacy, synergy, and resistance.

Aims and Objectives

Our project aims to:

• identify structural and biochemical determinants governing β-lactam antibiotic affinity, selectivity and resistance.
• understand how PBPs interact with their natural substrates during bacterial cell wall synthesis.
• evaluate novel compounds as dual inhibitors of PBPs and β-lactamases.
• apply advanced structural biology and computational simulations to investigate enzyme mechanisms and resistance pathways.
• generate knowledge that supports the optimisation of current and future antibacterial therapies against Klebsiella pneumoniae.

Methods

The fellowship combines microbiology, protein biochemistry, enzyme kinetics, structural biology (including X-ray crystallography, cryo-electron microscopy and emerging time-resolved approaches), and computational modelling. Protein structures will be linked with functional studies to reveal how antibiotics, inhibitors and natural substrates interact with PBPs and β-lactamases. Novel compounds will be tested against clinically relevant strains of Klebsiella pneumoniae to identify promising routes for future therapeutic development.

Together, these approaches will provide a comprehensive understanding of β-lactam action and resistance, informing the design of improved antibiotics and inhibitor combinations to combat antimicrobial resistance.

Principle investigator

• Dr Catherine Tooke, Lecturer & MRC Research Fellow, Department of Life Sciences