The development of antibiotics against Gram-negative pathogens is severely limited by the outer membrane barrier, which restricts drug entry and prevents compounds from reaching intracellular targets. While efflux pumps contribute to resistance, poor membrane penetration remains a fundamental bottleneck in antibiotic discovery. Our project addresses this challenge by developing predictive permeation rules—physicochemical and structural parameters that govern whether compounds can cross the Gram-negative envelope.
Using a multidisciplinary approach, we combine computational modelling, mass spectrometry, structural chemistry, and microbiology to define these rules. To support this effort, we use bisbiguanide analogues as chemical probes and apply our ERB technology to distinguish permeability barriers from efflux effects. Funded by the Biotechnology and Biological Sciences Research Council, this project aims to generate robust, predictive models that will guide rational antibiotic design.
Establishing clear permeation principles could transform antibiotic discovery by enabling chemists to design compounds with a higher likelihood of accumulating inside bacterial cells, ultimately accelerating the development of effective treatments for multidrug-resistant infections.