Abstract
Increasing the life-time of the acyl-enzyme complex formed between an inhibitor or drug molecule and the β-lactamase through chemical modifications of existing drug molecules is an important strategy towards developing inhibitors. In this direction, our group proposed a methyl-substituted β-lactam framework for the design of inhibitors for β-lactamases (J. Phys. Chem. B. 2018, 122, 4299). This unconventional design was guided by the transition state structure of the deacylation reaction of the acyl-enzyme complex. Here, we present a proof of principle study of this concept through detailed molecular simulations and free energy calculations. In particular, we improve the antimicrobial activity of the first-generation cephalosporin antibiotic, cephalothin, through C6-methylation. The proposed molecule, (6R,7R)-3-(acetyloxymethyl)-6-methyl-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate) slows down the deacylation of the acyl-enzyme complex 109-fold with no apparent effect on its binding to class-C β-lactamase and formation of the acyl-enzyme intermediate. The design strategy presented in this work can be further extended to all β–lactam antibiotics, like monobactams, carbapenems, cephalosporins, and penicillins.
Competing Interest Statement
The authors have declared no competing interest.