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Structure-Guided Design of a Fluorescent Probe for the Visualization of FtsZ in Clinically Important Gram-Positive and Gram-Negative Bacterial Pathogens.
Ferrer-González, Edgar; Fujita, Junso; Yoshizawa, Takuya; Nelson, Julia M; Pilch, Alyssa J; Hillman, Elani; Ozawa, Mayuki; Kuroda, Natsuko; Al-Tameemi, Hassan M; Boyd, Jeffrey M; LaVoie, Edmond J; Matsumura, Hiroyoshi; Pilch, Daniel S.
Afiliación
  • Ferrer-González E; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ, 08854, USA.
  • Fujita J; Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-087, Japan.
  • Yoshizawa T; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
  • Nelson JM; Department of Biotechnology, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Shiga, 525-8577, Japan.
  • Pilch AJ; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ, 08854, USA.
  • Hillman E; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ, 08854, USA.
  • Ozawa M; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ, 08854, USA.
  • Kuroda N; Department of Biotechnology, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Shiga, 525-8577, Japan.
  • Al-Tameemi HM; Department of Biotechnology, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Shiga, 525-8577, Japan.
  • Boyd JM; Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, 76 Lipman Drive, New Brunswick, NJ, 08901, USA.
  • LaVoie EJ; Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, 76 Lipman Drive, New Brunswick, NJ, 08901, USA.
  • Matsumura H; Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
  • Pilch DS; Department of Biotechnology, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Shiga, 525-8577, Japan. h-matsu@fc.ritsumei.ac.jp.
Sci Rep ; 9(1): 20092, 2019 12 27.
Article en En | MEDLINE | ID: mdl-31882782
Addressing the growing problem of antibiotic resistance requires the development of new drugs with novel antibacterial targets. FtsZ has been identified as an appealing new target for antibacterial agents. Here, we describe the structure-guided design of a new fluorescent probe (BOFP) in which a BODIPY fluorophore has been conjugated to an oxazole-benzamide FtsZ inhibitor. Crystallographic studies have enabled us to identify the optimal position for tethering the fluorophore that facilitates the high-affinity FtsZ binding of BOFP. Fluorescence anisotropy studies demonstrate that BOFP binds the FtsZ proteins from the Gram-positive pathogens Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae with Kd values of 0.6-4.6 µM. Significantly, BOFP binds the FtsZ proteins from the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii with an even higher affinity (Kd = 0.2-0.8 µM). Fluorescence microscopy studies reveal that BOFP can effectively label FtsZ in all the above Gram-positive and Gram-negative pathogens. In addition, BOFP is effective at monitoring the impact of non-fluorescent inhibitors on FtsZ localization in these target pathogens. Viewed as a whole, our results highlight the utility of BOFP as a powerful tool for identifying new broad-spectrum FtsZ inhibitors and understanding their mechanisms of action.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Bacterianas / Proteínas del Citoesqueleto / Colorantes Fluorescentes / Bacterias Gramnegativas / Bacterias Grampositivas Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Bacterianas / Proteínas del Citoesqueleto / Colorantes Fluorescentes / Bacterias Gramnegativas / Bacterias Grampositivas Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido