High dose of antibiotic colistin induces oligomerization of molecular chaperone HSP90

• Published in: Journal of biochemistry (Tokyo) Vol. 162; no. 1; pp. 27 - 36
• Main Authors: Togashi, Shuntaro, Takahashi, Kyosuke, Tamura, Arisa, Toyota, Ikumi, Hatakeyama, Shiori, Komatsuda, Atsushi, Kudo, Ikuru, Sasaki Kudoh, Erina, Okamoto, Tomoya, Haga, Asami, Miyamoto, Asuka, Grave, Ewa, Sugawara, Taku, Shimizu, Hiroaki, Itoh, Hideaki
• Format: Journal Article
• Language: English
• Published: England 01-07-2017
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Brain - drug effects; Brain - metabolism; Cell Survival - drug effects; Colistin - chemistry; Colistin - pharmacology; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Molecular Structure; Protein Aggregates - drug effects; Structure-Activity Relationship; Tumor Cells, Cultured; HSP90; molecular chaperone; polymixin; antibiotics; colistin
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvw104

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.