1. To understand the mechanism the Group I ß-lactamase AmpC. Outstanding questions include: the identity of the catalytic base, the direction of water attack, what separates a ß-lactam substrate from a ß-lactam inhibitor, and overall, how this information is encoded in the structure of the enzyme? ß-lactam analogs and transition-state analog boronic acids will be synthesized and their structures in complex with AmpC determined by x-ray crystallography. Mutant enzymes will be made to probe the enzyme side of the recognition event. It may be possible to characterize representative structures for each step in the catalytic pathway. The structures and energy analyses that emerge should provide a three-dimensional map for how ligand functionality is recognized by AmpC. This functional group map can be used in specific aim 2.2. To design non-ß-lactam inhibitors of serine ß-lactamases. The motivating idea is that structure can guide the discovery of non-ß-lactam inhibitors of ß-lactamases, and that such novel inhibitors would break the cycle of preevolved resistance mechanisms to which ß-lactams are subject. Guided by the functional group “map” investigated in specific aim 1, the following questions will be investigated: Can non-ß-lactam inhibitors be found that bind tightly to serine ß-lactamases? Would such non-ß-lactam inhibitors be susceptible to the suite of pre-evolved resistance mechanisms that face new ß-lactam inhibitors? Such non-ß-lactam inhibitors of ß-lactamases would not be hydrolysable by mutant ß-lactamases, and would not be expected to up-regulate the expression of ß-lactamases, as do many ßlactams. Two sorts of non-ß-lactam inhibitors will be investigated: transition-state analogs, and molecules discovered using molecular docking. The Ki values of the new inhibitors will be determined and their structures in complexes with AmpC will be solved by x-ray crystallography. The antimicrobial synergy of the new inhibitors will be evaluated, as will their ability to evade pre-evolved resistance mechanisms.
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|Titolo:||Strutture, Function and Inhibition of beta-Lactamases|
|Autori:||F. Prati; M. P. Costi; E. Caselli; F. Morandi; Brian Shoichet|
|Data di pubblicazione:||2001|
|Appare nelle tipologie:||Partecipazione a progetti di ricerca|
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