PBP Active Site Flexibility as the Key Mechanism for β-Lactam Resistance in Pneumococci |
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Authors: | Carlos Contreras-Martel Cécile Dahout-Gonzalez Alexandre Dos Santos Martins Andréa Dessen |
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Institution: | 1 Institut de Biologie Structurale Jean-Pierre Ebel, UMR 5075 (CEA, CNRS, UJF, PSB), 41 rue Jules Horowitz, F-38027 Grenoble, France 2 Lek Pharmaceuticals d.d. Drug Discovery, Verovskova 57, SI-1526 Ljubljana, Slovenia |
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Abstract: | Penicillin-binding proteins (PBPs), the main targets of β-lactam antibiotics, are membrane-associated enzymes that catalyze the two last steps in the biosynthesis of peptidoglycan. In Streptococcus pneumoniae, a major human pathogen, the surge in resistance to such antibiotics is a direct consequence of the proliferation of mosaic PBP-encoding genes, which give rise to proteins containing tens of mutations. PBP2b is a major drug resistance target, and its modification is essential for the development of high levels of resistance to piperacillin. In this work, we have solved the crystal structures of PBP2b from a wild-type pneumococcal strain, as well as from a highly drug-resistant clinical isolate displaying 58 mutations. Although mutations are present throughout the entire PBP structure, those surrounding the active site influence the total charge and the polar character of the region, while those in close proximity to the catalytic nucleophile impart flexibility onto the β3/β4 loop area, which encapsulates the cleft. The wealth of structural data on pneumococcal PBPs now underlines the importance of high malleability in active site regions of drug-resistant strains, suggesting that active site “breathing” could be a common mechanism employed by this pathogen to prevent targeting by β-lactams. |
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Keywords: | PBP penicillin-binding protein GT glycosyltransfer TP transpeptidation MAD multiple anomalous dispersion ESRF European Synchrotron Radiation Facility PDB Protein Data Bank |
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