posted on 2023-12-20, 18:14authored bySuhyeorn 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
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.