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OVERCOMING INHIBITOR RESISTANCE IN THE SHV BETA-LACTAMASEThomson, Jodi Michelle 08 June 2007 (has links)
No description available.
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Mechanisms of β- lactamase Inhibition and Heterotropic Allosteric Regulation of an Engineered β- lactamase-MBP Fusion ProteinKe, Wei January 2011 (has links)
No description available.
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Drug Design of β-Lactamase Inhibitors of the DBO-scaffold against OXA-48 : A Molecular Dynamics Study of Ligand Stability in the Michaelis ComplexLiljeholm, Linda January 2022 (has links)
The emergence of β-lactamase-mediated antibiotic resistance is one of the biggest threats in modern times. Combined with the discovery void of new forms of antibiotics, this sets the course toward a future where the efficacy of present-day health care will be jeopardized. To hinder the spread of β-lactamase-mediated antibiotic resistance, the development of the drug class β-lactamase inhibitors has been prioritized. The foremost candidate for development of this drug class, that has wide-spectrum inhibition of β-lactamases, is the clinically available avibactam of the diazabicyclooctane-scaffold (i.e., DBO-scaffold). However, the clinical applications of this inhibitor have been limited against one of the more rapidly spreading β-lactamases; OXA-48. In order to bolster the drug development of β-lactamase inhibitors of the DBO-scaffold, with good inhibitory activity toward OXA-48, DBO-ligands with different structure elements were analyzed for stability of the Michaelis Complex in the OXA-48 binding site using molecular dynamic simulations. The results indicate that elongation of the chain to the anionic group of the ligand combined with the addition of a methyl group to the DBO-ring was stabilizing for the productive position between the backbone hydrogens of Y211 and S70. The binding affinity was also estimated using the Linear Interaction Energy method, and an offset parameter of γ ≈ -19 kcal/mol was found and could represent the entropic differences of a flexible ligand-protein system. The results of this study may also indicate that the ligand stability of the Michaelis Complex is of minor consequence to the inhibition mechanism as a whole compared to the reaction rate.
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