Design of new benzoxazole-2-thione-derived inhibitors of Streptococcus pneumoniae hyaluronan lyase: structure of a complex with a 2-phenylindole

Glycobiology
Daniel J RigdenMark J Jedrzejas

Abstract

The bacterial hyaluronan lyases (Hyals) that degrade hyaluronan, an important component of the extracellular matrix, are involved in microbial spread. Inhibitors of these enzymes are essential in investigation of the role of hyaluronan and Hyal in bacterial infections and constitute a new class of antibiotics against Hyal-producing bacteria. Recently, we identified 1,3-diacetylbenzimidazole-2-thione and related molecules as inhibitors of streptococcal Hyal. One of such compounds, 1-decyl-2-(4-sulfamoyloxyphenyl)-1-indol-6-yl sulfamate, was co-crystallized in a complex with Streptococcus pneumoniae Hyal and its structure elucidated. The resultant X-ray structure demonstrates that this inhibitor fits in the enzymatic active site via interactions resembling the binding mode of the natural hyaluronan substrate. X-ray structural analysis also indicates binding interactions with the catalytic residues and those of a catalytically essential hydrophobic patch. An IC50 value of 11 microM for Hyal from Streptococcus agalactiae (strain 4755) qualifies this phenylindole compound as one of the most potent Hyal inhibitors known to date. The structural data suggested a similar binding mode for N-(3-phenylpropionyl)-benzoxazole-2-thione. This ...Continue Reading

Citations

Sep 6, 2012·Acta Crystallographica. Section D, Biological Crystallography·Bunzo MikamiKousaku Murata
Aug 2, 2011·European Journal of Medicinal Chemistry·Stephan BraunArmin Buschauer
Nov 16, 2010·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Andre KaesslerJoachim Jose
Jan 1, 2014·Chemistry : a European Journal·Kevin B MooreRobert A Vergenz
Mar 19, 2013·Journal of Photochemistry and Photobiology. B, Biology·Piyali MitraSamita Basu
May 9, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Oztekin AlgulJoachim Jose

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