S Khalid - BBSRC - Molecular Basis for Substrate Recognition

Bacterial membranes are notoriously impermeable - this is one of the reasons they are so difficult to beat with currently available antibiotics. This is leading to the widespread development of so-called 'superbugs'; bacteria that are resistant to many different antibiotics. This phenomenon provides modern healthcare with a serious problem. Pseudomonas aeruginosa is a human, animal and plant pathogen that is resistant to many different antibiotics. In humans, it tends to target those with already compromised immune systems, and is responsible for a large proportion of hospital acquired infections. Before we can embark on rational drug design to combat Pseudomonas aeruginosa, we must understand the routes via which the bacterial cell can be penetrated. Given that nature has had the benefit of years of evolution, it makes sense to exploit this by first trying to understand how molecules necessary for the survival of the bacterium, enter it. In this project we will use a range of computational methods supported by electrophysiology experiments by our collaborators, to elucidate the molecular pathways taken by dipeptides to enter the cell through the OprD protein. This protein is one member of the largest family of substrate-specific channel proteins located within the outer membrane of Pseudomonas aeruginosa. Recently reported studies reveal that using a combination of antibiotics (combination therapy) can be more effective than administering just one type. However the molecular-level consequences of combination therapy are currently completely unknown. Thus, in addition to studying OprD under 'normal' conditions, we will also explore how the protein behaves when its local environment is altered by polymyxin B1- an antibiotic.