TY - JOUR
T1 - Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library
AU - Park, Suhyeorn
AU - Fan, Jiayi
AU - Chamakuri, Srinivas
AU - Palaniappan, Murugesan
AU - Sharma, Kiran
AU - Qin, Xuan
AU - Wang, Jian
AU - Tan, Zhi
AU - Judge, Allison
AU - Hu, Liya
AU - Sankaran, Banumathi
AU - Li, Feng
AU - Prasad, B. V.Venkataram
AU - Matzuk, Martin M.
AU - Palzkill, Timothy
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2024/1/11
Y1 - 2024/1/11
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.3c01834
DO - 10.1021/acs.jmedchem.3c01834
M3 - Article
C2 - 38117688
AN - SCOPUS:85181027082
SN - 0022-2623
VL - 67
SP - 620
EP - 642
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -