Disruption And Resistance In Bacterial Cell Envelopes Challenged By Polymyxins

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Polymyxins are last-resort antibiotics for the treatment of infections caused by multi-drug-resistant pathogens such as carbapenemase-resistant E. coli. Polymyxins are known to target bacterial membranes, but how they kill Gram-negative bacteria remains poorly understood. The clinical use of polymyxins and other membrane-targeting antimicrobials is still restricted, due to associated host toxicity at near therapeutic concentrations. This highlights a significant gap in our biological understanding of the Gram-negative bacterial cell envelope and its barrier function, as well as the need for engineering polymyxins with improved activity and reduced host toxicity. We propose a research programme combining state-of-the-art biophysical, spectroscopic and microscopy techniques to determine how polymyxin antibiotics affect the outer and inner bacterial membranes and how this translates into cell envelope restructuring, disruption and bacterial cell death. We also investigate the molecular and structural impact of polymyxin on the bacterial envelope of adapted cells to understand the mechanism of self-protection and polymyxin resistance.

In this project, we investigate the perturbation of bacterial outer membranes by polymyxins. We look at outer membrane organisation, as well as molecular interactions that underpin outer membrane stability. We also look at the impact of polymyxins on the architecture, stability and integrity of inner bacterial membranes, challenged by polymyxins that have breached the outer membrane. We hypothesise that polymyxin may affect the exchange of lipopolysaccharide and lipid between the two membranes that is essential to maintaining the distinct morphology and essential physiological functions of the envelope membranes. Aiming to develop polymyxins with enhanced activity against resistant bacteria, we will characterise the molecular interface between polymyxin and its target, bacterial lipopolysaccharide from resistant strains.