Antimicrobial Resistance and Implications for the Twenty-First Century

doi:10.1007/978-0-387-72418-8

Emerging Infectious Diseases of the 21st Century 2008

DOI: 10.1007/978-0-387-72418-8

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Antimicrobial Resistance and Implications for the Twenty-First Century

Abstract: A Continuation Order plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

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Cited by 3 publications

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Deacylation Mechanism and Kinetics of Acyl–Enzyme Complex of Class C β-Lactamase and Cephalothin

Tripathi

Nair

2016

J. Phys. Chem. B

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Understanding the molecular details of antibiotic resistance by the bacterial enzymes β-lactamases is vital for the development of novel antibiotics and inhibitors. In this spirit, the detailed mechanism of deacylation of the acyl-enzyme complex formed by cephalothin and class C β-lactamase is investigated here using hybrid quantum-mechanical/molecular-mechanical molecular dynamics methods. The roles of various active-site residues and substrate in the deacylation reaction are elucidated. We identify the base that activates the hydrolyzing water molecule and the residue that protonates the catalytic serine (Ser64). Conformational changes in the active sites and proton transfers that potentiate the efficiency of the deacylation reaction are presented. We have also characterized the oxyanion holes and other H-bonding interactions that stabilize the reaction intermediates. Together with the kinetic and mechanistic details of the acylation reaction, we analyze the complete mechanism and the overall kinetics of the drug hydrolysis. Finally, the apparent rate-determining step in the drug hydrolysis is scrutinized.

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Deacylation Mechanism and Kinetics of Acyl–Enzyme Complex of Class C β-Lactamase and Cephalothin

Tripathi

Nair

2016

J. Phys. Chem. B

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Thermodynamic and Kinetic Stabilities of Active Site Protonation States of Class C β-Lactamase

Tripathi

Nair

2012

J. Phys. Chem. B

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By employing computationally intensive molecular dynamics simulations using hybrid quantum-mechanical/molecular-mechanical approach, we analyze here the kinetic and thermodynamic stabilities of various active site protonation states of a fully solvated class C β-lactamase. We report the detailed mechanism of proton transfer between catalytically important active site residues and the associated free energy barriers. In the apoenzyme, significant structural changes are associated with the proton transfer, and the orientations of active site residues are distinctly different for various protonation states. Among several propositions on the protonation state of the apoprotein, we find that the one with Tyr150 deprotonated and both Lys67 and Lys315 residues being protonated is the most stable one, both thermodynamically and kinetically. However, the equilibrium structure at room temperature is a dynamic one, with Lys315Hζ delocalized between Tyr150Oη and Lys315Nζ. Of great importance, the kinetic and thermodynamic stability of protonation states are significantly affected on noncovalently complexing with cephalothin, an antibiotic molecule. The equilibrium structure of the enzyme-substrate (precovalent) complex has a dynamic protonation state where a proton shuttles frequently between the Tyr150Oη and Lys67Nζ. We examine here the genesis of the manifold change in stability at the molecular level. The importance of our observations toward understanding the reactivity of the enzyme is discussed and experimental observations are rationalized.

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Antimicrobial Activity of 11 Insects Extracts Against Multi Drug Resistant (MDR) Strains of Bacteria and Fungus

Shao

et al. 2019

IOP Conf. Ser.: Earth Environ. Sci.

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Antimicrobial Resistance and Implications for the Twenty-First Century

Abstract: A Continuation Order plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

Cited by 3 publications

References 1,063 publications

Deacylation Mechanism and Kinetics of Acyl–Enzyme Complex of Class C β-Lactamase and Cephalothin

Deacylation Mechanism and Kinetics of Acyl–Enzyme Complex of Class C β-Lactamase and Cephalothin

Thermodynamic and Kinetic Stabilities of Active Site Protonation States of Class C β-Lactamase

Antimicrobial Activity of 11 Insects Extracts Against Multi Drug Resistant (MDR) Strains of Bacteria and Fungus

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