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J. Biol. Chem., Vol. 280, Issue 48, 39709-39715, December 2, 2005

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Novel Inhibitors of Bacterial Cytokinesis Identified by a Cell-based Antibiotic Screening Assay^*

Neil R. Stokes, Jörg Sievers, Stephanie Barker, James M. Bennett, David R. Brown, Ian Collins, Veronica M. Errington, David Foulger, Michelle Hall, Rowena Halsey, Hazel Johnson, Valerie Rose, Helena B. Thomaides, David J. Haydon, Lloyd G. Czaplewski1, and Jeff Errington2

From the Prolysis Ltd., Oxford University Begbroke Science Park, Oxfordshire, OX5 1PF, United Kingdom and Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom

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.

Received for publication, June 21, 2005 Accepted for publication September 12, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported by grants from the Biotechnology and Biological Sciences Research Council for work on cell division and sporulation.

¹ To whom correspondence should be addressed: Prolysis Ltd., Oxford University Begbroke Science Park, Sandy Lane, Yarnton, Oxfordshire, OX5 1PF, United Kingdom. Tel.: 44-1865-854700; Fax: 44-1865-854799; E-mail: lloyd.czaplewski{at}prolysis.com.

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