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Science 19 September 2008:
Vol. 321. no. 5896, pp. 1673 - 1675
DOI: 10.1126/science.1159961
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Reports

An Inhibitor of FtsZ with Potent and Selective Anti-Staphylococcal Activity

David J. Haydon,1 Neil R. Stokes,1* Rebecca Ure,1 Greta Galbraith,1 James M. Bennett,1 David R. Brown,1 Patrick J. Baker,2 Vladimir V. Barynin,2 David W. Rice,2 Sveta E. Sedelnikova,2 Jonathan R. Heal,3 Joseph M. Sheridan,3 Sachin T. Aiwale,4 Pramod K. Chauhan,4 Anil Srivastava,4 Amit Taneja,4 Ian Collins,1 Jeff Errington,1,5 Lloyd G. Czaplewski1

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian β-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.

1 Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.
2 Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
3 Prosarix, Newton Hall, Cambridge CB22 7ZE, UK.
4 Jubilant Chemsys, B-34, Sector-58, Noida 201301, India.
5 Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

* To whom correspondence should be addressed. E-mail: neil.stokes{at}prolysis.com

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Tubulin-Like RepX Protein Encoded by the pXO1 Plasmid Forms Polymers In Vivo in Bacillus anthracis.
P. Akhtar, S. P. Anand, S. C. Watkins, and S. A. Khan (2009)
J. Bacteriol. 191, 2493-2500
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