RESUMEN
The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy. The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described. Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.
Asunto(s)
Antibacterianos/síntesis química , Proteínas Portadoras/química , Proteínas de Ciclo Celular/química , Proteínas de Escherichia coli/química , Indoles/síntesis química , Piperidinas/síntesis química , Antibacterianos/farmacología , División Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Escherichia coli/citología , Escherichia coli/efectos de los fármacos , Indoles/farmacología , Concentración 50 Inhibidora , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.