Chemphyschem. 2026 May 27;27(10):e70414. doi: 10.1002/cphc.70414.

ABSTRACT

Serine $\beta –$ lactamases are bacterial enzymes that cause antibiotic resistance by rapid hydrolysis of $\beta –$ lactam antibiotics. Development of efficient covalent inhibitors for serine $\beta$ -lactamases requires an understanding of the factors that can increase the free energy barrier for hydrolysis of the covalent-intermediate formed by the $\beta –$ lactamases and the ligands. We show that steric factors introduced by methyl substitution at a suitable position in an existing $\beta –$ 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 $\beta –$ lactamases.

PMID:42174373 | DOI:10.1002/cphc.70414