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The study aims to develop inhibitors for carbapenemases, specifically KPC-2 and NDM-1, to combat antibiotic resistance.

February 28, 2026ACS Omega0 citationsOpen Access

Structure-Based Design of Reversible, Quinoline-2(1 H )-one Inhibitors of Serine- and Metallo-Carbapenemases

LJLian M. C. Jacobs PJPriyadarshini Jaishankar JZJeffrey Zheng

Key Points

The study aims to develop inhibitors for carbapenemases, specifically KPC-2 and NDM-1, to combat antibiotic resistance.
Conducted structure-based design of quinoline-2(1H)-one inhibitors.
Assessed binding determinants at the active sites of KPC-2 and NDM-1.
Executed systematic substitution of the quinoline scaffold to evaluate binding properties.
Performed biophysical and computational studies on ligand binding stoichiometry.
Identified N1 and C7 positions in the scaffold as tolerant to diverse modifications.
C3-methyl and C6-fluoro substitutions significantly influence binding mode and affinity.
Determined that only one of the two ligand binding events is crucial for effective NDM-1 inhibition.
Current inhibitors demonstrate limited whole-cell activity but provide insights for future drug targeting.

Abstract

Carbapenems are essential β-lactam antibiotics whose clinical utility is now threatened by emerging carbapenemases, including the Class A serine β-lactamase KPC-2 and the Class B metallo-β-lactamase NDM-1. Here, we describe a comprehensive, structure-based assessment of active-site binding determinants for KPC-2 and NDM-1 in the context of reversible, noncovalent inhibition by a quinoline-2(1H)-one phosphonate scaffold. Systematic substitution of the scaffold core revealed the N1 and C7 positions as most tolerant of diverse substitution, while the less tolerant C3 and C6 positions nevertheless drive affinity and binding mode when modified with a C3-methyl or C6-fluoro substituent, respectively. We also describe biophysical and computational studies aimed at determining the pharmacological significance of the 2:1 ligand binding stoichiometry observed in several NDM-1 complex structures, concluding that only one of these binding events is relevant for potent NDM-1 inhibition. Although the current inhibitors lack significant whole-cell activity, the structural and biochemical findings described provide valuable information for the targeting of evolutionarily and mechanistically diverse carbapenemases.

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