Bactericidal antibiotics induce programmed metabolic toxicity

Abstract

The misuse of antibiotics has led to the development and spread of antibiotic resistance in clinically important pathogens. These resistant infections are having a significant impact on treatment outcomes and contribute to approximately 25,000 deaths in the U.S. annually. If additional therapeutic options are not identified, the number of annual deaths is predicted to rise to 317,000 in North America and 10,000,000 worldwide by 2050. Identifying therapeutic methodologies that utilize our antibiotic arsenal more effectively is one potential way to extend the useful lifespan of our current antibiotics. Recent studies have indicated that modulating metabolic activity is one possible strategy that can impact the efficacy of antibiotic therapy. In this review, we will address recent advances in our knowledge about the impacts of bacterial metabolism on antibiotic effectiveness and the impacts of antibiotics on bacterial metabolism. We will particularly focus on two studies, Lobritz, et al. (PNAS, 112(27): 8173-8180) and Belenky et al. (Cell Reports, 13(5): 968-980) that together demonstrate that bactericidal antibiotics induce metabolic perturbations that are linked to and required for bactericidal antibiotic toxicity.

Keywords: antibiotic resistance and tolerance; antibiotics; metabolism; reactive oxygen species (ROS).

Figure 1. FIGURE 1: A model relating the impact of respiratory metabolism on bactericidal toxicity.

Metabolically quiescent cells are tolerant to antibiotics whereas metabolically active bacteria are more susceptible. In metabolically active cells bactericidal antibiotics interact with their primary targets to directly induce toxicity. In addition to direct toxicity this initial target dependent damage also leads to the elevation of respiratory activity through the induction of futile metabolic cycles and other mechanisms. Elevated redox metabolism leads to elevated oxygen consumption and induction of ROS production as both a metabolic byproduct and as a result of disordered respiratory activity. ROS and other oxidants then damage cellar components such as DNA, protein and lipids and thereby contribute to bacterial death.