Suhyeorn Park; Jiayi Fan; Srinivas Chamakuri; Murugesan Palaniappan; Kiran Sharma; Xuan Qin; Jian Wang; Zhi Tan; Allison Judge; Liya Hu; Banumathi Sankaran; Feng Li; B. V. Venkataram Prasad; Martin M. Matzuk; Timothy Palzkill
J. Med. Chem., 2024, 67(1), 620–642
https://doi.org/10.1021/acs.jmedchem.3c01834

Abstract

β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the β-lactamase enzyme–substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 106 compounds, each containing a carboxylic acid or a tetrazole as an enzyme recognition element, was designed, constructed, and used to identify OXA-48 and NDM-1 inhibitors with micromolar to nanomolar potency. Further optimization led to NDM-1 inhibitors with increased potencies and biological activities. This work demonstrates that the carboxylate-binding pocket-targeting DECL, designed based on substrate binding information, aids in inhibitor identification and led to the discovery of novel non-β-lactam pharmacophores for the development of β-lactamase inhibitors for enzymes of different structural and mechanistic classes.