Effects of 4-Br-A23187 on Bacillus subtilis cells and unilamellar vesicles reveal it to be a potent copper ionophore.

Autor: Senges CHR; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Warmuth HL; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Vázquez-Hernández M; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Uzun HD; Department of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany., Sagurna L; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Dietze P; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Schmidt C; Inorganic and Organometallic Medicinal Chemistry, Faculty of Life Sciences, Technical University Braunschweig, Braunschweig, Germany.; Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel., Mücher B; Department of Zoology and Neurobiology, Ruhr University Bochum, Bochum, Germany., Herlitze S; Department of Zoology and Neurobiology, Ruhr University Bochum, Bochum, Germany., Krämer U; Molecular Genetics and Physiology of Plants, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany., Ott I; Inorganic and Organometallic Medicinal Chemistry, Faculty of Life Sciences, Technical University Braunschweig, Braunschweig, Germany., Günther Pomorski T; Department of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany., Bandow JE; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
Jazyk: angličtina
Zdroj: Proteomics [Proteomics] 2022 Sep; Vol. 22 (17), pp. e2200061. Date of Electronic Publication: 2022 Jun 27.
DOI: 10.1002/pmic.202200061
Abstrakt: Ionophores are small molecules or peptides that transport metal ions across biological membranes. Their transport capabilities are typically characterized in vitro using vesicles and single ion species. It is difficult to infer from these data which effects ionophores have on living cells in a complex environment (e.g., culture medium), since net ion movement is influenced by many factors including ion composition of the medium, concentration gradients, pH gradient, and protein-mediated transport processes across the membrane. To gain insights into the antibacterial mechanism of action of the semisynthetic polyether ionophore 4-Br-A23187, known to efficiently transport zinc and manganese in vitro, we investigated its effects on the gram-positive model organism Bacillus subtilis. In addition to monitoring cellular ion concentrations, the physiological impact of treatment was assessed on the proteome level. 4-Br-A23187 treatment resulted in an increase in intracellular copper levels, the extent of which depended on the copper concentration of the medium. Effects of copper accumulation mirrored by the proteomic response included oxidative stress, disturbance of proteostasis, metal and sulfur homeostasis. The antibiotic effect of 4-Br-A23187 is further aggravated by a decrease in intracellular manganese and magnesium. A liposome model confirmed that 4-Br-A23187 acts as copper ionophore in vitro.
(© 2022 The Authors. Proteomics published by Wiley-VCH GmbH.)
Databáze: MEDLINE