There are several formidable challenges in antimicrobial drug discovery that make this field intellectually appealing. First, there is an “innovation gap” – no new broad-spectrum class of antibiotics has been discovered in the past 40 years. Moreover no antibiotic has ever been able to completely sterilize an infection due to the presence of persisters cells.
Our group’s goal is to discover sterilizing antibacterials.
- One approach is to identify prodrugs – compounds that have no activity on their own, but get converted into reactive compounds inside a bacterial cell by bacteria-specific enzymes. The aim is to discover prodrug antibiotics by screening compounds against strains overexpressing potential activating enzymes.
- Another approach is to emulate the strategy used by medicinal plants to eliminate persisters. Plants such as Golden Seal make a membrane-acting antimicrobial berberine which is extruded from a pathogen by Multidrug Resistence (MDR) pumps. Plants also make MDR inhibitors, and berberine + MDR inhibitor produces a potent sterilizing combination. The aim is to identify MDR inhibitors that will be effective in humans and develop a combination therapeutic for sterilizing infections.