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Computer-Aided Design of Agents That Inhibit the cep Quorum-Sensing System of Burkholderia cenocepacia

Department of Microbiology, Institute of Plant Biology, University of Zürich, Zürich, Switzerland,¹ Department of Microbiology, Technical University of Munich, Freising, Germany,² 4SC AG, Martinsried, Germany³

Received 2 August 2005/ Returned for modification 27 September 2005/ Accepted 25 October 2005

Recent research has provided evidence that interference with bacterial cell-to-cell signaling is a promising strategy for the development of novel antimicrobial agents. Here we report on the computer-aided design of novel compounds that specifically inhibit an N-acyl-homoserine lactone-dependent communication system that is widespread among members of the genus Burkholderia. This genus comprises more than 30 species, many of which are important pathogens of animals and humans. Over the past few years, several Burkholderia species, most notably Burkholderia cenocepacia, have emerged as important opportunistic pathogens causing severe pulmonary deterioration in persons with cystic fibrosis. As efficient treatment of Burkholderia infections is hampered by the inherent resistance of the organisms to a large range of antibiotics, novel strategies for battling these pathogens need to be developed. Here we show that compounds targeting the B. cenocepacia signaling system efficiently inhibit the expression of virulence factors and attenuate the pathogenicity of the organism.

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