Overview
Research Themes
Our research is centred around two broad themes:
1. Conjugative systems in bacteria:
Our lab is interested in understanding how bacteria use secretion systems for exchanging genetic material through conjugation to maintain genomic diversity and achieve saltational evolution into pathogenic species causing widespread infectious diseases related mortality. This exchange of genetic material between bacteria, also referred to as horizontal gene transfer (HGT) is fundamental to the dissemination of antimicrobial resistance (AMR) within bacteria, a formidable biomedical challenge, and an area of active research. After working extensively with gram- bacteria and studying Type-4 secretion systems (T4SS) involved in classical conjugation, our current focus is to understand how gram+ mycobacteria, a family of considerable importance in infectious diseases and AMR undertakes a distinctive form of HGT (distributive conjugal transfer (DCT)) to facilitate its evolution into pathogenic mycobacteria and develop antimicrobial resistance.
The overarching aim of this research program is to establish a structural basis for DCT by characterizing the multimegadalton membrane-integrated Type-7 secretion systems (T7SS) and associated complexes using a combination of biophysical chemistry and structural methods with a long-term vision of developing targeted antibiotics against these systems.
2. Bacteriophage defense mechanisms in bacteria:
Research interest in bacterial-bacteriophage interactions has come to the centerstage due to its importance in bacterial evolution, as gene editing tools (CRISPR-Cas) and most importantly in the development of phage therapies to treat or prevent hard-to-treat bacterial infections and combat antibiotic resistance. Although this strategy has many advantages, the main drawback is the risk of encountering or favouring the emergence of phage resistant/insensitive bacterial pathogens, molecular mechanisms of which remain completely unexplored. In this arms-race between microorganisms, bacteria have evolved numerous defence strategies to combat phage infections like the Restriction-Modification Systems (RM), DNA degradation systems and CRISPR-Cas Systems, Abortive-infection systems (Abi) and cGAS-STING pathway.
Our lab is particularly interested in characterizing the Abortive infection (Abi) system which is usually a measure of last resort as it involves the bacterial cell committing suicide after sensing infection before the phage can complete its replication cycle. Although a plethora of Abi systems are now known, we are particularly interested in dissecting how λ-lysogenic prophage encoded RexA/RexB Abi system prevents infection of other bacteriophages like the T4, T5 and T7 phages in E. coli. Research on Abi systems in bacteria is expected to accelerate the design of better bacteriophage-based therapies against persistent pathogens like M. tuberculosis,
M. ulcerans, M. abscessus, C. difficile, P. aeruginosa, S. aureus, A. baumannii and K. pneumoniae.
Karsten Schneider ©
Strategy
Methods
Our goal is to understand how these biological processes work and to achieve this, we use a multi-disciplinary approach combining
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Structural biology: X-ray crystallography and cryo-EM
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Molecular cloning
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Membrane-protein biochemistry
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Biophysical (mass spectrometry, EPR, FRET, Cross-linking)
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Cross-linking and fractionation strategies
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In-sillico (AL/ML-led molecular modelling)
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Molecular dynamics
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Live-cell imaging and fluorescence microscopy techniques
David Goodsell @ Scripps ©
Environment
Our Community and collaborations
Mycobacterial Conjugative Secretion system Project:
We collaborate extensively within the University of Leicester (UoL) ecosystem: Departments of Molecular Cell Biology (MCB), Respiratory Sciences (RS) and the Leicester Tuberculosis Research Group (LTRG) along-with inter-institutional collaboration with University College London (UCL) and University of Birmingham (UoB) for functional in-vivo characterization of conjugative systems.
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Bacterial Phage defence project
We collaborate with Department of Genetics and Genome Biology (GGB) and National Centre for Phage Research, UoL for our abortive-infection (Abi) project.
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Structural biology instrumentation
We access the resources available within the Midlands Cryo-EM Facility and Biophysics facility within LISCB (Leicester Institute of Structural and Chemical Biology) for structural and biophysical characterization of protein-protein and protein-DNA complexes of interest.