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Publication Abstract from PubMed

beta-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important beta-lactam class of antibiotics. The OXA-48 and NDM-1 beta-lactamases cause resistance to the last-resort beta-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel beta-lactamase inhibitors. We exploited the beta-lactamase enzyme-substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all beta-lactamases. A library of 10(6) 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-beta-lactam pharmacophores for the development of beta-lactamase inhibitors for enzymes of different structural and mechanistic classes.

Exploiting the Carboxylate-Binding Pocket of beta-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library.,Park S, Fan J, Chamakuri S, Palaniappan M, Sharma K, Qin X, Wang J, Tan Z, Judge A, Hu L, Sankaran B, Li F, Prasad BVV, Matzuk MM, Palzkill T J Med Chem. 2023 Dec 20. doi: 10.1021/acs.jmedchem.3c01834. PMID:38117688^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.