title: Chaperonins fight aminoglycoside-induced protein misfolding and promote short-term tolerance in Escherichia coli.
abstract: For almost half of a century, we have known that aminoglycoside antibiotics corrupt ribosomes, causing translational misreading, yet it remains unclear whether or not misreading triggers protein misfolding, and possible effects of chaperone action on drug susceptibilities are poorly understood. Here, we show that aminoglycosides cause cytosolic protein misfolding and that chaperonin GroEL/GroES overexpression counters this defect. During aminoglycoside exposure to exponential cultures, chaperonin overexpression protected the bacterial membrane potential, rescued cell growth, and facilitated survival, whereas inhibition of chaperonin expression sensitized bacteria. Overexpression of the DnaK/DnaJ/GrpE chaperone system similarly facilitated survival but did not promote growth of aminoglycoside-treated bacteria. Inhibition of chaperonin expression sensitized bacteria to aminoglycosides as measured by reduced minimum inhibitory concentrations, whereas GroEL/GroES overexpression did not increase minimum inhibitory concentrations. Our observations establish misfolding of cytosolic proteins as an effect of aminoglycoside action and reveal that chaperones, chaperonins in particular, help bacteria cope during early exposure to these drugs.
authors: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, 200 Copenhagen, Denmark.
authors: Lise
authors: L
authors: Goltermann
authors: Liam
authors: L
authors: Good
authors: Thomas
authors: T
authors: Bentin
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D018835:Chaperonin 10 / Q000235:genetics / Q000378:metabolism*; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects*
chemical_list: D000617:Aminoglycosides; D018835:Chaperonin 10; D018834:Chaperonin 60; C494635:DnaJ protein, E coli; D029968:Escherichia coli Proteins; C489400:GrpE protein, E coli; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C063842:dnaK protein, E coli