A Common Mechanism May Underlie the Bactericidal Action of Antibiotics
Abstract and Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University, School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: The three major classes of bactericidal antibiotics (aminoglycosides, cell wall synthesis inhibitors, and bacterial gyrase inhibitors) stimulate the production of hydroxyl radicals, which contribute to cell death. The mechanism of hydroxyl radical formation induced by bactericidal antibiotics results from oxidative damage/cell death pathway involving the tricarboxylic acid (TCA) cycle, depletion of NADPH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction.
Source: Kohanski MA, et al. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007;130:797-810.
In a series of elegant experiments, kohanski et al demonstrated that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate hydroxyl radical formation in bacteria. In contrast, bacteriostatic agents do not do this. All of the bactericidal antibiotics studied utilized internal iron from iron-sulfur complexes to stimulate Fenton-mediated hydroxyl radical formation mediated by the TCA cycle, and are associated with a transient depletion of NADPH. Additionally, following treatment with bactericidal antibiotics, hydroxyl radical-mediated DNA damage resulted in initiation of the DNA damage response system (SOS response). Furthermore, the bactericidal action of kanamycin was demonstrated to be potentiated by knockout of the recA gene, disabling the SOS response.
Commentary
I always enjoy reading a basic science paper that serves to explain phenomena we observe in the lab and at the bedside. This paper reported a number of carefully designed experiments that elucidated the unifying mechanism by which all three classes of bactericidal antibiotics (cell wall active agents, β-lactams, and glycopeptides/lipopeptides, aminoglycosides, and fluoroquinolones) exert their bactericidal action against bacteria. This same group later expanded these experiments to examine in greater detail the mechanism of bactericidal action of aminoglycosides.1
These latter studies showed that aminoglycosides, by inducing mistranslation and misfolding of membrane proteins, cause oxidative stress and cell death through a two-component system. A second group has recently demonstrated similar findings, including demonstration that protein misfolding and aggregation induce changes in specific host proteins involved in lipid metabolism and oxidative stress, a reduction in the membrane permeability, as well as a rearrangement of its lipid composition.2
References:
- Kohanski MA, et al. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell. 2008;135:679-690.
- Ami D, et al. Effects of recombinant protein misfolding and aggregation on bacterial membranes. Biochim Biophys Acta. 2009;1794:263-269
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content