title: High dose of antibiotic colistin induces oligomerization of molecular chaperone HSP90.
abstract: Colistin is an antimicrobial cationic peptide that belongs to the polymyxin family. Colistin was clinically used for the treatment of gram-negative infections but fell out of favour because of its significant side effects including neurotoxicity and nephrotoxicity. More recently, colistin has been regarded as one of the important options for nosocomial infections caused by multidrug resistant bacteria. Mechanisms of both the side effect onset of the drug and the side effect reduction are yet to be elucidated. In this study, we identified the specific binding protein of colistin using an affinity column chromatography. Colistin binds to the molecular chaperone HSP90. Although colistin slightly suppressed the chaperone activity of HSP90, there are no effects on the ATPase activity for a low concentration of colistin. Interestingly, colistin-induced aggregation of HSP90 via the N-domain. As for the cell viability of the SHSY5Y cell, the cell viability decreased to approximately 80% by the colistin 300 μM. However, the cell viability recovered to approximately 100% by adding ATP dosage. The same result was obtained by dot blot assay using anti-HSP90 antibody. Our results may help to understand the side effect mechanism of colistin.
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Togashi
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Toyota
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Hematology, Nephrology, Rheumatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Komatsuda
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Ikuru
authors.initials: I
authors.lastname: Kudo
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Sasaki Kudoh
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Haga
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Miyamoto
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Ewa
authors.initials: E
authors.lastname: Grave
authors.affiliation: Department of Spinal cord and Spine Surgery, Research Institute for Brain and Blood Vessels-Akita, 010-0874 Akita, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Sugawara
authors.affiliation: Department of Neurosurgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Life Science, Akita University Graduate School of Engineering Science, Akita 010-8502, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003091:Colistin / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D018841:HSP90 Heat-Shock Proteins; D066329:Protein Aggregates; D003091:Colistin
keywords: HSP90; antibiotics; colistin; molecular chaperone; polymixin