Interplay between bacterial multidrug efflux and outer membrane permeability creates an unexpected vulnerability towards antibiotics.

Antibiotic resistance (AMR) is global health emergency that increasingly challenges our ability to treat life-threatening infections. To tackle this major threat to our health, it is critical to develop new therapeutics that are less prone to AMR development. Equal efforts should also be directed towards developing novel drugs that can supress the resistance development and even re-sensitise bacterial pathogens towards existing antibiotics. In Gram-negative pathogens, two key processes that drive AMR is multidrug efflux, which allows the cells to expel toxic substances such as antibiotics, and the diffusion barrier formed by outer membrane, which prevents the entry of many antibacterial compounds. Consequently, both inhibitors of multidrug efflux pumps, and compounds that disrupt the outer membrane permeability function are under intense drug development efforts.
Recently, we made the surprising discovery that the multidrug efflux and outer membrane permeability barrier function are surprisingly closely interlinked. Whilst the biological processes that underpin the crosstalk between outer membrane permeability and drug efflux are still poorly characterised, the phenomenon is directly relevant for the drug development for two distinct reasons: (i) the crosstalk makes it difficult to distinguish between efflux inhibitor and outer membrane permeabilising compounds using the current methods but (ii) argues for strong potential for synergy between these two classes of drug candidates.
Studying this process will provide exciting insights into the mechanisms through which bacteria evolve and acquire antibiotic resistance, but also allows us to identify vulnerabilities that can be exploited for the development of drugs and drug combinations that are less prone to AMR development.
In this collaborative and interdisciplinary project between the groups of Henrik Strahl and Manuel Banzhaf (Newcastle) and Gary Sharples (Durham), the crosstalk between outer membrane permeability...