title: An inhibitor of FtsZ with potent and selective anti-staphylococcal activity.
abstract: FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.
authors.affiliation: Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Haydon
authors.forename: Neil R
authors.initials: NR
authors.lastname: Stokes
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ure
authors.forename: Greta
authors.initials: G
authors.lastname: Galbraith
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.forename: David R
authors.initials: DR
authors.lastname: Brown
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Baker
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Barynin
authors.forename: David W
authors.initials: DW
authors.lastname: Rice
authors.forename: Sveta E
authors.initials: SE
authors.lastname: Sedelnikova
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Heal
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sheridan
authors.forename: Sachin T
authors.initials: ST
authors.lastname: Aiwale
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Chauhan
authors.forename: Anil
authors.initials: A
authors.lastname: Srivastava
authors.forename: Amit
authors.initials: A
authors.lastname: Taneja
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Jeff
authors.initials: J
authors.lastname: Errington
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Czaplewski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001412:Bacillus subtilis / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial; D008024:Ligands; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D008024:Ligands; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles; D014404:Tubulin