Drug Discovery
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.
Members:
Gabriele CasadeiDanuta "Danka" Tomkiewicz
Michael La Fleur
Josh Williams
Laura Fleck
Our group's goal is to discover sterilizing antibacterials.
1. 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.
Lewis Nature Reviews Microbiology 5, 48–56 (January 2007)
2. 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.
Fig. 2. The effect of BERBERINE, INF55 and HYBRID SS14 on the survival of nematodes infected with E. faecalis. (A) Chemical structure of antimicrobial (berberine), MDR inhibitor (INF55) and hybrid molecule (SS14) composed of covalently linked berberine and MDR inhibitor. (B) Experimental set-up (C) Effect of berberine, INF55 and hybrid on the survival of E. faecalis infected nematodes – C. elegans (Ball ASC Chem Biol 2006, Moy PNAS 2006).