مؤتمر
Interactions mediating the positioning of mercapto-phosphonate inhibitors in the active site of metallo-beta-lactamases
| العنوان: | Interactions mediating the positioning of mercapto-phosphonate inhibitors in the active site of metallo-beta-lactamases |
|---|---|
| المؤلفون: | Lassaux, Patricia, Delbrück, Heinrich, Gulea, Michaela, Kupper, Michaël, Hoffmann, Kurt, Galleni, Moreno, Bebrone, Carine |
| المصدر: | ECCMID, Vienne, Austria [AT], 10-13 avril 2010 |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | Metallo-b-lactamases (MBL) represent an emerging problemdue to their capacity to hydrolyze almost all b-lactam antibiotics,including last generation cephalosporins and carbapenems. Due to thepresence of two chelating functions (sulfanyl and phosphonato), the mercaptophosphonic acids (phosphorous analogues of mercaptocarboxylic acids) are potential candidates for MBL inhibitors.Methods: The inhibitory effect of 14 mercapto-phosphonate derivativesagainst representatives of the three subclasses of MBLs (VIM-4 (B1),CphA (B2) and L1 (B3)) was previously reported [1]. Here, in order to determine the interactions mediating the positioning of the inhibitorsin the active site of each enzyme, crystallographic and docking studieswere performed with 10a and 18, both inhibitors being active against thethree subclasses.Results: The crystallographic structure of the CphA-10a and CphA-18indicated that the sulphur atom of 10a and the phosphonato group of18 interact with the zinc ion respectively. Molecular modelling on theVIM-4 (B1) and FEZ-1 (B3) enzymes with 10a and 18 also brought tolight different binding modes depending on the enzyme and the inhibitor,consistent with the crystallographic structures.Conclusions: The investigation of mercapto-phosphonate derivativesas MBL inhibitor has allowed us to find potent inhibitors active onrepresentative members of all the three MBL subclasses. Moreover, onthe basis of structural and modelling data, the inhibitory strength of thesecompounds will be improved further.Reference(s)[1] Lassaux P., Hamel M., Gulea M., Mercuri P., Horsfall L.,Bebrone C., Gaumont A-C., Frère J., Galleni M. Mercaptophosphonatecompounds as broad-spectrum inhibitors of the metallob-lactamases, Abstract number: 1732_295, ECSMID 2007. |
| نوع الوثيقة: | conference paper not in proceedings http://purl.org/coar/resource_type/c_18cp conferencePaper peer reviewed |
| اللغة: | English |
| URL الوصول: | https://orbi.uliege.be/handle/2268/302145 |
| رقم الأكسشن: | edsorb.302145 |
| قاعدة البيانات: | ORBi |
| الوصف غير متاح. |