Common Mechanisms of Bacterial Cell Death Induced by Antibiotics

Common Mechanisms of Bacterial Cell Death Induced by Antibiotics

Antibiotics bind to their targets, disrupting normal cellular metabolism, including the tricarboxylic acid (TCA) cycle. This depletes intracellular NADH, which is paired with a commensurate rise in the production of reactive oxygen species such as peroxide and superoxide. These reactive oxygen species interact with Fe²⁺ via Fenton chemistry to generate highly toxic oxygen radicals, which react with DNA and proteins, resulting in death of bacteria.

The new work by Kohanski et al. provides a theory of bacterial cell death induced by antibiotics wherein the inhibition of an essential process—for example, cell-wall synthesis—results in an increase in the concentration of intracellular hydroxyl radicals and damage to vital cell components (DNA, proteins, membranes). Furthermore, this work nicely builds on research showing that antibiotics such as ciprofloxacin also induce the SOS response and that the SOS response is a key step in the development of antibiotic resistance.

The SOS response includes the production of proteins involved in the repair of DNA damage such as RecA and protein folding agents such as chaperones. The repair of DNA damage is frequently accompanied by tolerance of minor gene mutations that can contribute to antibiotic resistance. Cell death and antibiotic resistance may therefore be connected through the production of hydroxyl radicals.