Molecular dissection of horizontal gene transfer mechanisms in mycobacteria

Supervisors

• Dr Abhinav Koyamangalath Vadakkepat (akv10@leicester.ac.uk)
• Professor John Schwabe
• Professor Gurdyal Besra School of Biosciences (SBS), University of Birmingham

A fully funded PhD position is available within the lab of Dr Abhinav KV at Leicester Institute of Structural and Chemical Biology (LISCB), University of Leicester, UK to carry out structural studies on large macromolecular machines that undertake horizontal gene transfer (HGT) in mycobacteria. This project has important implications on global efforts to fight infections caused by persistent pathogens and combating antimicrobial-resistance (AMR).

About the project

Uncover the molecular mysteries of AMR – your research can make a life-saving difference!

Antibiotics have revolutionized bacterial-infection treatments, prolonging human life by over a decade. However, the rampant spread of antibiotic-resistance (AMR) genes poses a grave threat. AMR-related deaths are projected to dominate global mortality by 2050, potentially reaching 10 million annually and yet the associated molecular-mechanisms remain unexplored. Given that secretion-systems are the primary drivers of conjugation and AMR, it is essential to understand how they function. Our recent work elucidated the structure of a Type-4 secretion system (T4SS) which are large membrane-integrated nanomachines involved in conjugation and is pivotal in 80% of all AMR dissemination. Beyond well-studied classical conjugation in E. coli, poorly understood systems like Distributive-Conjugal-Transfer (DCT) in gram+ Mycobacteriaceae, a family responsible for global infectious disease-related mortality and multi/extreme drug-resistance necessitates investigation. Our research program aims to establish the structural foundation of this process, employing molecular cloning, biophysical and structural methods and cryo-EM.

This interdisciplinary project, conducted in the lab of Dr Abhinav KV (LISCB/MCB) and Professor. Gurdyal Besra (University of Birmingham) offers a vibrant interdisciplinary research environment and access to world-class research facilities for structural biology and cryo-EM. It welcomes candidates passionate about structural biology, protein structure-function, host-pathogen interactions, and infectious diseases. You will learn molecular cloning, advanced membrane-protein purification techniques, enabling in-vitro and in-vivo structural elucidation of these multi-megadalton nanomachines using cryo-EM and cryo-electron tomography (cryo-ET). The project encompasses various interdisciplinary techniques, including biophysics, cross-linking mass-spectrometry, X-ray crystallography, integrative structural biology and live-cell imaging. Access to LISCB's cutting-edge microscopy infrastructure, including the state-of-the-art Titan Krios 300 keV microscope, enhances this opportunity. Alongwith University of Leicester resources and mentorship provided by Professor John Schwabe (LISCB), the project leverages the expertise of our collaborators at University College London and University of Texas, USA.

To know more, visit our website and contact Dr Abhinav KV (akv10@leicester.ac.uk) for informal enquiries.