[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: A novel series of DHODH inhibitors was developed based on a lead which was obtained by a docking procedure and a medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method to yield low nanomolar inhibitors.