Biomedical Vacation Scholarship, ‘The design of peptidic inhibitors of efflux pumps in gram-negative bacteria’

Antibiotic resistance in gram-negative bacteria can occur due to drug efflux by protein transporters such as AcrB. Efflux pump inhibitors (EPI) can restore efficacy of antibiotics, however known EPIs also produce in vivo toxicity, which could be detrimental to the host. We aim to design peptides that have structural features that are present in known EPIs, and thus having ability to inhibit efflux
pumps without any adverse effects. Molecular dynamics simulation will be carried out to generate 3D structures of peptides to be docked into the binding site of an efflux pump. In silico predicted binding affinities will be used as a criteria for selection of peptides with highest potential to affect the efflux pump function. The effects of the binding of peptides on the binding site conformation, and therefore the efflux pump's function, will be explored by molecular dynamics simulation of a peptide – pump complex.
The peptides with the highest in silico affinity for efflux pump and potential to affect its function will be proposed for further in silico toxicology evaluation, as well as in vitro evaluation of their inhibitory potential and toxicity.