Antibiotic efficacy is linked to bacterial cellular respiration

Abstract

Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes-the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.

The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

“…SigE represents one of the major players in the M. tuberculosis stress response and has a fundamental role in the adaptation to surface and oxidative stresses (16,17). During antibiotic treatment, bacteria are subjected to several stresses (including oxidative and surface stresses), depending on the drug's mechanism of action (18)(19)(20)(21). To determine whether SigE has a protective role under these conditions, we subjected an M. tuberculosis H37Rv-derived sigE-null mutant, its H37Rv parental strain, and a complemented strain (in which a wild-type copy of sigE was reintroduced in an ectopic locus of the genome) to treatment with increasing concentrations of several drugs using the resazurin microtiter assay (REMA).…”

Bioluminescent Reporters for Rapid Mechanism of Action Assessment in Tuberculosis Drug Discovery

“…Although unresolved, the prevailing model posits that bactericidal antibiotics dysregulate core metabolic and respiratory functions, resulting in damage to macromolecules within the cell, including both DNA and cell wall components, that is ultimately cytotoxic (50,51). This notion suggested the possibility that all cidal agents might be associated with a DNA damage response at some stage during the extended (7-to 12-day) duration of our assays.…”

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

“…Expression of genes involved in metabolism and respiration is upregulated in the presence of aminoglycosides, and metabolic rates appear to increase (20,81). Increased respiration byproducts may therefore be central to the bacterial killing ability of aminoglycosides; indeed, decreased oxygen availability can dampen bactericidal efficiency (82). Furthermore, modulation of antioxidant response pathways also affects antibiotic efficacy.…”