title: Identification of anti-tuberculosis agents that target the cell-division protein FtsZ.
abstract: Antibiotic resistance to Mycobacterium tuberculosis is a growing problem. Therefore, development of new anti-tuberculosis antibiotics is urgent for the control of tuberculosis (TB) infections. FtsZ, the homolog of eukaryotic tubulin, is a GTPase that assembles into cytokinetic Z rings essential for cell division in prokaryotic cells. FtsZ (filamentous temperature-sensitive protein Z) polymerizes in a GTP-dependent manner, and polymerization of FtsZ forms into dynamic protofilaments. In this study, we screened 20,000 compounds to identify inhibitors of GTPase activity of M. tuberculosis FtsZ. We found that 297F inhibited GTPase and polymerization of FtsZ, and reduced the amount of FtsZ polymers. Furthermore, 297F has anti-TB activity with low cytotoxicity and shows no antibacterial activities toward other Gram-positive or Gram-negative strains. In vitro, 297F also induced filamentation in Mycobacterium smegmatis. All results suggest that 297F inhibits bacterial proliferation by targeting M. tuberculosis FtsZ and it may be useful as a lead compound for developing anti-TB agents.
authors.affiliation: State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ningyu
authors.initials: N
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D020558:GTP Phosphohydrolases