A common mechanism of cellular death induced by bactericidal antibiotics. Export

@article{citeulike:1640634, 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.}, address = {Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Boston University School of Medicine, Boston, MA 02118, USA.}, author = {Kohanski, Michael A. and Dwyer, Daniel J. and Hayete, Boris and Lawrence, Carolyn A. and Collins, James J.}, citeulike-article-id = {1640634}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.cell.2007.06.049}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0092867407008999}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17803904}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17803904}, day = {7}, doi = {10.1016/j.cell.2007.06.049}, issn = {0092-8674}, journal = {Cell}, keywords = {antimicrobials}, month = {September}, number = {5}, pages = {797--810}, posted-at = {2009-08-05 09:27:08}, priority = {2}, title = {A common mechanism of cellular death induced by bactericidal antibiotics.}, url = {http://dx.doi.org/10.1016/j.cell.2007.06.049}, volume = {130}, year = {2007} }

TY - JOUR ID - citeulike:1640634 L3 - citeulike-article-id:1640634 N2 - 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. IS - 5 JF - Cell SN - 0092-8674 AD - Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Boston University School of Medicine, Boston, MA 02118, USA. EP - 810 TI - A common mechanism of cellular death induced by bactericidal antibiotics. VL - 130 SP - 797 KW - antimicrobials AU - Kohanski, Michael AU - Dwyer, Daniel AU - Hayete, Boris AU - Lawrence, Carolyn AU - Collins, James PY - 2007/09/07/ UR - http://dx.doi.org/10.1016/j.cell.2007.06.049 ER -