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Steric Induced Inhibition of Serine β -Lactamase Catalyzed Hydrolysis
Vaishali Thakkur1, Chandan Kumar Das1,2, Shivani Verma1
1Indian Institute of Technology Kanpur, India.
Abstract:
Serine lactamases are bacterial enzymes that cause antibiotic resistance by rapid hydrolysis of lactam antibiotics. Development of efficient covalent inhibitors for serine -lactamases requires an understanding of the factors that can increase the free energy barrier for hydrolysis of the covalent-intermediate formed by the lactamases and the ligands. We show that steric factors introduced by methyl substitution at a suitable position in an existing lactam drug can slow down its hydrolysis by sterically hindering the hydrolytic water molecule from approaching the reaction site. Through molecular simulations, we demonstrate that a weak cephalosporin, like cephalothin, can be revitalized with this strategy. An increase in the lifetime of the acyl-enzyme complex leads to the inhibition of serine lactamases.
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