Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death.
Aminoglycoside antibiotics, such as gentamicin and kanamycin, directly target the ribosome, yet the mechanisms by which these bactericidal drugs induce cell death are not fully understood. Recently, oxidative stress has been implicated as one of the mechanisms whereby bactericidal antibiotics kill bacteria. Here, we use systems-level approaches and phenotypic analyses to provide insight into the pathway whereby aminoglycosides ultimately trigger hydroxyl radical formation. We show, by disabling systems that facilitate membrane protein traffic, that mistranslation and misfolding of membrane proteins are central to aminoglycoside-induced oxidative stress and cell death. Signaling through the envelope stress-response two-component system is found to be a key player in this process, and the redox-responsive two-component system is shown to have an associated role. Additionally, we show that these two-component systems play a general role in bactericidal antibiotic-mediated oxidative stress and cell death, expanding our understanding of the common mechanism of killing induced by bactericidal antibiotics.
Kohanski
Michael A
MA
Department of Biomedical Engineering, Center for BioDynamics, and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA.
Dwyer
Daniel J
DJ
Wierzbowski
Jamey
J
Cottarel
Guillaume
G
Collins
James J
JJ
D000617:Aminoglycosides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D017665:Hydroxyl Radical; D008565:Membrane Proteins / Q000187:drug effects*; D008954:Models, Biological; D008957:Models, Genetic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014176:Protein Biosynthesis / Q000187:drug effects*; D011489:Protein Denaturation; D017510:Protein Folding
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; D017665:Hydroxyl Radical