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

  • Science. 2008 Sep 19;321(5896):1673-5. doi: 10.1126/science.1159961.
David J Haydon  1 ,  Neil R Stokes ,  Rebecca Ure ,  Greta Galbraith ,  James M Bennett ,  David R Brown ,  Patrick J Baker ,  Vladimir V Barynin ,  David W Rice ,  Sveta E Sedelnikova ,  Jonathan R Heal ,  Joseph M Sheridan ,  Sachin T Aiwale ,  Pramod K Chauhan ,  Anil Srivastava ,  Amit Taneja ,  Ian Collins ,  Jeff Errington ,  Lloyd G Czaplewski
Affiliations
  • 1. Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.
PMID: 18801997 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.

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