Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

Abstract

Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics—quinolones, aminoglycosides, and β-lactams—cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic–induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-L-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

“…Sorts for each time point were performed in triplicate and subjected to RNA-Seq analysis. Bactericidal antibiotics cause oxidative stress in mammalian cells, leading us to speculate that sublethal concentrations of neomycin may cause changes in gene expression unrelated to hair cell death (41). To control for this nonspecific effect, we examined gene expression in GFP − cells in the presence or absence of neomycin (Fig.…”

Testing the optimality properties of a dual antibiotic treatment in a two-locus, two-allele model

“…Not only are high antibiotic dosages toxic [9,19], they can disrupt the ecological stability of the commensal microbiota, allowing pathogens to colonize the host [20]. A strategy for increasing drug potency while decreasing drug concentration is the use of multidrug cocktails [21].…”

Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death

“…In bacteria, aminoglycosides induce oxidative damage through disruption of the citric acid cycle and electron transport chain (19,20). Although the impact of ROS generation on bactericidal effects is unclear, it has been suggested that these antibiotics can induce cellular dysfunction within mammalian cells through mitochondrial generation of ROS (21). As mitochondria generally impose the largest influence to the overall oxidative state of the cell through their housing and regulation of the citric acid cycle and electron transport chain components (22,23), they are a likely source of ROS during aminoglycoside-induced hair cell death.…”