Dual Effect: High NADH Levels Contribute to Efflux-Mediated Antibiotic Resistance but Drive Lethality Mediated by Reactive Oxygen Species
Alejandro Arce‐Rodríguez, Debbie Pankratz, Matthias Preuße, Pablo I. Nikel, Susanne Häußler
Abstract
The emergence of antibiotic resistance has become one of the major threats to public health. A better understanding of antimicrobial killing mechanisms promises to uncover new ways to resensitize bacteria to commonly used antibiotics. In this context, there is increasing evidence that the metabolic status of the cell plays a fundamental role in reactive oxygen species (ROS)-mediated cell death. In this work, we artificially manipulated the redox balance in Pseudomonas aeruginosa by the expression of two orthologous enzymes. We found that the increase of intracellular NADH concentrations leads to higher antibiotic resistance but also generates a burst in the production of ROS that amplified antimicrobial killing. Our work suggests that the combination of bactericidal antibiotics with agents that disturb the cellular redox homeostasis could significantly enhance antibiotic killing via sensitization of pathogens to currently available antibiotics.