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J. Biol. Chem., Vol. 280, Issue 20, 19948-19957, May 20, 2005

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Ofloxacin-like Antibiotics Inhibit Pneumococcal Cell Wall-degrading Virulence Factors^*

Carlos Fernández-Tornero, Ernesto García¶, Beatriz de Pascual-Teresa||, Rubens López¶, Guillermo Giménez-Gallego**, and Antonio Romero**

From the Departamento de Estructura y Función de Proteínas and ^¶Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, C/Ramiro de Maeztu, 9, 28040 Madrid, Spain and the ^||Departamento de CC Químicas, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Boadilla del Monte, 28668 Madrid, Spain

The search for new drugs against Streptococcus pneumoniae (pneumococcus) is driven by the 1.5 million deaths it causes annually. Choline-binding proteins attach to the pneumococcal cell wall through domains that recognize choline moieties, and their involvement in pneumococcal virulence makes them potential targets for drug development. We have defined chemical criteria involved in the docking of small molecules from a three-dimensional structural library to the major pneumococcal autolysin (LytA) choline binding domain. These criteria were used to identify compounds that could interfere with the attachment of this protein to the cell wall, and several quinolones that fit this framework were found to inhibit the cell wall-degrading activity of LytA. Furthermore, these compounds produced similar effects on other enzymes with different catalytic activities but that contained a similar choline binding domain; that is, autolysin (LytC) and the phage lytic enzyme (Cpl-1). Finally, we resolved the crystal structure of the complex between the choline binding domain of LytA and ofloxacin at a resolution of 2.6 Å. These data constitute an important launch pad from which effective drugs to combat pneumococcal infections can be developed.

Received for publication, February 2, 2005 , and in revised form, March 9, 2005.

^* This work was supported in part by Ministerio de Educación y Ciencia (Spain) Grants BIO2001-1724 and BMC2003-00074. 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.

The atomic coordinates and structure factors (code 2BML) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Supported by a Ph.D. fellowship from the Ministerio de Educación y Ciencia. Present address: European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, BP 181, 38042 Grenoble, France.

^** Both authors contribute equally to this work.

To whom correspondence should be addressed. Tel.: 34-91-8373112 (ext. 4244); Fax: 34-91-5360432; E-mail: romero{at}cib.csic.es.

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