Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay.
The continuous emergence of antibiotic resistance demands that novel classes of antibiotics continue to be developed. The division machinery of bacteria is an attractive target because it comprises seven or more essential proteins that are conserved almost throughout the bacteria but are absent from humans. We describe the development of a cell-based assay for inhibitors of cell division and its use to isolate a new inhibitor of FtsZ protein, a key player in the division machinery. Biochemical, cytological, and genetic data are presented that demonstrate that FtsZ is the specific target for the compound. We also describe the effects of more potent analogues of the original hit compound that act on important pathogens, again at the level of cell division. The assay and the compounds have the potential to provide novel antibiotics with no pool of pre-existing resistance. They have provided new insight into cytokinesis in bacteria and offer important reagents for further studies of the cell division machinery.
Stokes
Neil R
NR
Prolysis Ltd., Oxford University Begbroke Science Park, Oxfordshire, OX5 1PF, United Kingdom.
Sievers
Jörg
J
Barker
Stephanie
S
Bennett
James M
JM
Brown
David R
DR
Collins
Ian
I
Errington
Veronica M
VM
Foulger
David
D
Hall
Michelle
M
Halsey
Rowena
R
Johnson
Hazel
H
Rose
Valerie
V
Thomaides
Helena B
HB
Haydon
David J
DJ
Czaplewski
Lloyd G
LG
Errington
Jeff
J
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001412:Bacillus subtilis; D001426:Bacterial Proteins / Q000378:metabolism; D002455:Cell Division; D003001:Cloning, Molecular; D048749:Cytokinesis / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D020558:GTP Phosphohydrolases / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D008826:Microbial Sensitivity Tests / Q000379:methods*; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D010647:Phenyl Ethers / Q000494:pharmacology*; D013696:Temperature; D013997:Time Factors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; C507542:PC 58538; D010647:Phenyl Ethers; D015091:beta-Alanine; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases