Drug Efflux Pump Inhibitors

DESCRIPTION (provided by applicant): The overall commercial aim of this project is to discover and develop new drugs that block drug efflux pumps in multidrug-resistant bacteria and tumors. The Phase I project brings together two new sources or technologies: 1) the development of new, versatile screens for drug candidates that block multidrug efflux pumps, and 2) screening a new library of unusual marine bacterial metabolites for their ability to inhibit a variety of multidrug efflux pumps. Cell-based screens of representative multidrug efflux pumps from four families or superfamilies of membrane transporters will be conducted with crude and partially purified extracts extracted from a library of marine bacteria. The bacteria will be cultured on standard media and unusual marine organic substrates to increase diversity of secondary metabolites. The Phase I project will identify media and culture conditions for the greatest expression of the most promising metabolites, and optimize conditions for the screens. The Phase II project will seek to purify the drug efflux pump inhibitors and determine their mechanisms of activity. The innovative screening technology is versatile for a variety of cloned transport proteins and it will be useful for the discovery of drug candidates to combat drug-resistant infections and some drug-resistant cancers. PROPOSED COMMERCIAL APPLICATION: New marine-derived drugs against multidrug-resistant bacteria and tumors. Screening technology for drug efflux pump inhibitors. Marine extract libraries for screens against other therapeutic targets. New specialty sources of culture media (marine organic substrates).