(288a) Metabolic Strategies to Enhance Antibiotics Action

With the ever-increasing incidence of antibiotic-resistant infections and a weak pipeline of new antibiotics, our antibiotic arsenal is in danger of becoming obsolete. To address this issue, both novel antibiotics and novel strategies to enhance the effectiveness of current antibiotics need to be developed. Recently, our lab discovered a common mechanism of cellular death induced by bactericidal antibiotics (Kohanski et al 2007). Three major classes of bactericidal antibiotics all stimulated production of the hydroxyl radical, which is a highly reactive oxygen species (ROS) generated as a by-product of aerobic respiration and Fenton chemistry. This phenomenon contributed to cell death and was independent of the primary drug-target interaction. Since hydroxyl radical production results from aberrant metabolic activity, we devised metabolic strategies to increase ROS production and potentiate currently available antibiotics. Our approach integrates ROS-generating reactome data, phenotype screens, and Flux Balance Analysis (FBA) in order to model opportunistic ROS production. With this method, we were able to identify modes of metabolism (e.g., nutrient availability in the media) that influence ROS production, and thereby, enhance or impair antibiotic action.

Kohanski et al (2007) Cell Sep 7;130(5):797-810.