Drug Discovery

The Center uses both experimental and virtual screening approaches to identify new compounds with antibacterial properties.

Novel inhibitors of AcrAB-TolC efflux pump from Escherichia coli

Efflux pump inhibitors (EPIs) are emerging alternative therapeutics that have the potential to revive the activities of existing antibiotics and to control the spread of antibiotic resistance. The inner membrane transporter AcrB has hitherto been a focus of efforts to identify EPIs. The Center analyzes the periplasmic membrane fusion protein (MFP), AcrA, as an allosteric target for multidrug efflux inhibition. AcrA and its analogs enable the extrusion of antibiotics across the outer membrane by assembling into a hexameric structure on the periplasmic surface of AcrB and creating a sealed tunnel for antimicrobials to reach the outer membrane channel TolC. This assembly is highly dynamic and serves both structural and several functional roles. The Center developed a joint experimental-computational ligand screening approach of general applicability in the discovery of inhibitors for periplasmic targets. See video with Jeremy Smith and Helen Zgurskaya discussing this discovery.

Abdali, N., et al., Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump. ACS Infect Dis, 2017. 3(1): p. 89-98. DOI: 10.1021/acsinfecdis.6b00167

Condensin Inhibitors

Condensins play a central role in chromosome packing and segregation and have been genetically validated in various disease models. Rybenkov group recently discovered the first known condensin inhibitors. The Center is working on optimization of these compounds for the use as chemical probes and preclinical development.