The combination of primary and secondary damages accounts for the lethality of bactericidal antibiotics. Binding of bactericidal antibiotic cripples the essential function of its target and engenders antibiotic-specific primary damage. In response, bacteria activate repair factors and replace corrupted targets, an energy-costly effort which entails a massive metabolic remodeling (1). Cells gradually exhaust available adenosine 50-triphosphate (ATP), reducing equivalents, and increase production of toxic waste products, such as reactive oxygen species (ROS). The ensuing secondary damage, as well as the amplification of the primary damage, is a general attribute of the bacterial response to different classes of bactericidal antibiotics and lethal stressors (2). Without it, cells actually tolerate bactericidal antibiotics well, and the growth inhibition becomes reversible once the antibiotic is removed. Blocking protein synthesis with a bacteriostatic inhibitor (1), decreasing the activity of the ATP synthase complex with subinhibitory concentrations of bedaquiline (3), or disabling cellular respiration with a genetic knockout of the cytochrome complex (4) all confer a high level of tolerance to bactericidal antibiotics. However, new studies suggest that slow or no bacterial growth, per se, are neither necessary nor sufficient for antibiotic tolerance (5). Taking ATP or the nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide ratio as a proxy for a metabolic state, the lethality of bactericidal antibiotics is more strongly correlated to it than to the growth rate. The more resources bacteria can spend on a failing response, the more potent are the bactericidal antibiotics.
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