Phenotypic screening of compound libraries as a platform for the identification of antibiotic adjuvants: Identification of colistin adjuvants from a natural product library

Abstract

The identification of antibiotic adjuvants, small molecules that potentiate the activity of conventional antibiotics, provides an orthogonal approach to the development of new antibiotics in the fight against drug resistant bacterial infections. Methods to identify novel adjuvants could potentially aid efforts to overcome the increasing prevalence of resistance and stave off the onset of a "post-antibiotic era." Phenotypic whole cell screens allow for the identification of hits with the necessary properties to access their biomolecular target, and may also facilitate the discovery of novel adjuvant targets. A phenotypic screening platform is outlined, in which a natural product library was explored for activity with antibiotics from several mechanistically distinct classes against clinically important bacterial species. General approaches to delineating the mechanism of action of hit compounds identified from phenotypic screens are described, followed by specific approaches to uncovering the mechanism of action of the colistin adjuvants identified from the natural product screen.

Keywords: Antibiotic adjuvant; Colistin; Multi-drug resistance; Natural product; Phenotypic screen.