An inhibitor of FtsZ with potent and selective anti-staphylococcal activity

Science. 2008 Sep 19;321(5896):1673-5. doi: 10.1126/science.1159961.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Bacillus subtilis / chemistry
  • Bacillus subtilis / drug effects*
  • Bacillus subtilis / genetics
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Cell Division / drug effects
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / antagonists & inhibitors*
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Drug Resistance, Bacterial / genetics
  • Drug Resistance, Multiple, Bacterial
  • Ligands
  • Methicillin Resistance
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Staphylococcal Infections / drug therapy*
  • Staphylococcus aureus / chemistry
  • Staphylococcus aureus / drug effects*
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use
  • Tubulin / chemistry
  • Tubulin / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Cytoskeletal Proteins
  • FtsZ protein, Bacteria
  • Ligands
  • PC190723
  • Pyridines
  • Thiazoles
  • Tubulin

Associated data

  • GENBANK/EU914258
  • GENBANK/EU914259
  • GENBANK/EU914260
  • GENBANK/EU914261
  • GENBANK/EU914262
  • GENBANK/EU914263
  • GENBANK/EU914264
  • PDB/2VXY
  • PDB/R2VXYSF