A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics

Abstract

Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.

Peroxide‐Sensing Transcriptional Regulators in Bacteria

“…There is a growing realization of the role of peroxide-sensing regulators in adapting to this environmental shift through the control of processes such as virulence factor expression (74,90) and biofilm formation (99,119). Furthermore, the lethality of some antibiotics is due, at least in part, to increased production of ROS (58), and it has been demonstrated that the levels of oxidative stress protective enzymes can affect antibiotic resistance levels (6). Therefore, a detailed understanding of the mechanisms and physiological functions of oxidative stress responsive regulators will further our understanding of bacterial adaptation to environmental changes in general and is likely to shed new light on aspects of many clinically important processes.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…There is growing awareness that many antibiotics affect multiple modes of bacterial physiology by means that are beyond direct inhibition of currently understood primary targets of each antibiotic class (306), and evidence suggests that QS is one alternative target of antibiotics in some species. Therefore, it is worth discussing interactions between antibiotics and bacterial cell-cell communication.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Recently, it also became evident that a number of drugs, such as antiinflammatory drugs, statins, and antibiotics, which supposedly aimed at different targets in unlike disorders, have the regulation of oxidative stress as a prominent mode of action, thus potentiating the widespread awareness of the role that oxidative stress plays in several diseases and injuries (3,27,47,55,64,155,175,188,209,228,312,336). Superoxide dismutase is an endogenous and first-line-of-defense enzyme that eliminates superoxide by catalyzing its dismutation into O 2 and H 2 O 2 (119,120,212,240).…”