Glycobiology Advance Access originally published online on April 25, 2006
Glycobiology 2006 16(8):757-765; doi:10.1093/glycob/cwj116
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Design of new benzoxazole-2-thione-derived inhibitors of Streptococcus pneumoniae hyaluronan lyase: structure of a complex with a 2-phenylindole
3 Children’s Hospital Oakland Research Institute, Oakland, CA 94609; 4 School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK; and 5 Institute of Pharmacy, University of Regensburg, 93040 Regensburg, Germany
1 To whom correspondence should be addressed; e-mail: stefan.dove{at}chemie.uni-regensburg.de
2 To whom correspondence should be addressed; e-mail: mjedrzejas{at}chori.org
Received on March 15, 2006; accepted on April 18, 2006
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 µM 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 new compound’s inhibitory properties were confirmed resulting in discovery of yet another Hyal inhibitor (IC50 of 15 µM). These benzoxazole-2-thiones constitute a new class of inhibitors of bacterial Hyals and are well suited for further optimization of their selectivity, potency, and pharmacokinetic properties.
Key words: antimicrobials / hyaluronidase / molecular mechanism / pneumococci / spreading factor
* These authors contributed equally to this work.