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

Daniel J. Rigden, Alexander Botzki, Masatoshi Nukui, R. Brandon Mewbourne, Ejvis Lamani, Stephan Braun, Erwin von Angerer, Günther Bernhardt, Stefan Dove, Armin Buschauer, Mark J. Jedrzejas
2006 Glycobiology  
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 1,3diacetylbenzimidazole-2-thione and related molecules as inhibitors of streptococcal Hyal. One of such compounds,
more » ... famoyloxyphenyl)-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 IC 50 value of 11 mM 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 (IC 50 of 15 mM). 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.
doi:10.1093/glycob/cwj116 pmid:16638841 fatcat:6ghxruowtrdrrcyunmucdfj7ba