8SQF

OXA-48 bound to inhibitor CDD-2725

Summary for 8SQF

• Entry DOI: 10.2210/pdb8sqf/pdb
• Descriptor: Beta-lactamase, (1M)-3'-(benzyloxy)-5-hydroxy[1,1'-biphenyl]-3,4'-dicarboxylic acid, BICARBONATE ION, ... (4 entities in total)
• Functional Keywords: carbapenemase, beta-lactamase, small molecule, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 61730.18

Authors

Park, S.,Judge, A.,Fan, J.,Sankaran, B.,Prasad, B.V.V.,Palzkill, T. (deposition date: 2023-05-04, release date: 2024-01-03, Last modification date: 2024-01-17)

Primary citation

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, B.V.V.,Matzuk, M.M.,Palzkill, T.
Exploiting the Carboxylate-Binding Pocket of beta-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library.
J.Med.Chem., 67:620-642, 2024

PubMed 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 10 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.

PubMed: 38117688
DOI: 10.1021/acs.jmedchem.3c01834

Experimental method

X-RAY DIFFRACTION (2.3 Å)