An inhibitor of FtsZ with potent and selective anti-staphylococcal activity.
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.
Haydon
David J
DJ
Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.
Stokes
Neil R
NR
Ure
Rebecca
R
Galbraith
Greta
G
Bennett
James M
JM
Brown
David R
DR
Baker
Patrick J
PJ
Barynin
Vladimir V
VV
Rice
David W
DW
Sedelnikova
Sveta E
SE
Heal
Jonathan R
JR
Sheridan
Joseph M
JM
Aiwale
Sachin T
ST
Chauhan
Pramod K
PK
Srivastava
Anil
A
Taneja
Amit
A
Collins
Ian
I
Errington
Jeff
J
Czaplewski
Lloyd G
LG
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
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D008024:Ligands; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles; D014404:Tubulin