Abstract
ABSTRACTIn light of the antibiotic crisis, emerging strategies to sensitize bacteria to available antibiotics should be explored. Several studies on the mechanisms of killing suggest that bactericidal antibiotic activity is enforced through the generation of reactive oxygen species (ROS-lethality hypothesis). Here, we artificially manipulated the redox homeostasis of the model opportunistic pathogen Pseudomonas aeruginosa using specific enzymes that catalyze either the formation or oxidation of NADH. Increased NADH levels led to the activation of antibiotic efflux pumps and high levels of antibiotic resistance. However, higher NADH levels also resulted in increased intracellular ROS and amplified antibiotic killing. Our results demonstrate that growth inhibition and killing activity are mediated via different mechanisms. Furthermore, the profound changes in bioenergetics produced low-virulence phenotypes characterized by reduced interbacterial signaling controlled pathogenicity traits. Our results pave the way for a more effective infection resolution and add an antivirulence strategy to maximize chances to combat devastating P. aeruginosa infections while reducing the overall use of antibiotics.
Highlights
IMPORTANCE The emergence of antibiotic resistance has become one of the major threats to public health
We increased the NADH-to-NAD1 ratio via the expression of the C. boidinii formate dehydrogenase (FDH) (FDH1Cb) in P. aeruginosa grown in the presence
Bactericidal antibiotics lead to the cellular accumulation of toxic reactive oxygen species, which in turn make an important contribution to cell death
Summary
IMPORTANCE 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 addition to an intensified search for novel antimicrobials, one might explore possibilities to sensitize bacteria to currently available antibiotics This could lead to a more effective killing of the infecting bacteria and reduce the total amount of antibiotics used. J. Collins research group provided new evidence that the activity of bactericidal antibiotics is linked to reactive oxygen species (ROS) production [5]. As the chemistries of protons and electrons are closely linked, it may be not possible to decipher whether the bactericidal effect of an antibiotic is due to oxidative stress, the disruption of pH homeostasis, or both
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