PAGE M; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 757 (abstract no. 641).
Hoffman-La Roche Ltd., Basel, Switzerland.
The structure and mechanism of beta-lactamases and penicillin-binding proteins have been investigated in detail using X-ray crystallography, infrared spectroscopy, calorimetry and kinetic analysis by stopped-flow spectroscopy. These studies have provided insights into the catalytic cycle of these enzymes that can be used as a basis for the design of potent inhibitors that can be used alone, or in combination with existing antibiotics, to overcome deeply entrenched resistance to beta-lactams. The studies have produced a number of surprises, amongst which is the indication of significant conformational changes as an integral part of the catalytic cycle of both families of enzymes. As yet, it have not been possible to identify the structural basis for these changes by X-ray crystallography with beta-lactams, their interpretation is not straightforward because of the restricted movement in crystals. Thus, a completely "rational" approach to drug design for these enzymes is some way beyond our current capabilities and intuition and serendipity remain as important as ever.
Publication Types:
Keywords:
- Anti-Bacterial Agents
- Crystallography, X-Ray
- Drug Design
- Kinetics
- Penicillin-Binding Proteins
- antagonists & inhibitors
- beta-Lactamases
- beta-Lactams
Other ID:
UI: 102246021
From Meeting Abstracts