Saturday, September 8, 2007

Groundbreaking News - Insight into the Mechanisms of Action of Antibiotics

One of the major threats to global health today is antimicrobial resistance. An important finding was reported by Kohanski and others this month in the journal Cell. Researchers from Boston have discovered that there is a common mechanism of bacterial cell death induced by three different classes of bactericidal antibiotics. This common mechanism involves reactive oxygen intermediates or “oxygen free radicals.” This finding provides hope for finding new methods of combating infection. Scientists can focus on methods of amplifying the oxidative damage cellular death pathway or on inhibiting cellular repair mechanisms.

NADH oxidases located in the plasma membrane catalyze the formation of superoxide (O2-) anions. Superoxide is dismutated to hydrogen peroxide and molecular oxygen by superoxide dismutase (SOD). Catalase can convert hydrogen peroxide to water. A Fenton reaction can take place in the presence of peroxidases, leading to the formation of hydroxyl (OH-) radicals.

Here is the abstract to the intriguing article:
(From - Kohanski et al.
Cell, Vol 130, 797-810, 07 September 2007)
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.


Anonymous said...

Yes, really. So happens.

Anonymous said...

Not your business!