Structural Basis of Metallo-β-lactamase Inhibition by N-Sulfamoylpyrrole-2-carboxylates.

Alistair J. M. Farley,Patrick Rabe,Yuri Ermolovich,Karina Calvopiña,Jürgen Brem,Christopher J. Schofield,Tharindi Panduwawala,Fredrik Björkling

doi:10.1021/acsinfecdis.1c00104

Alistair J. M. Farley, Patrick Rabe + Show 6 more

Open Access

https://doi.org/10.1021/acsinfecdis.1c00104

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Abstract

Metallo-β-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of β-lactam antibiotics except monobactams. While serine-β-lactamase (SBL) inhibitors (e.g., clavulanic acid, avibactam) are established for clinical use, no such MBL inhibitors are available. We report on the synthesis and mechanism of inhibition of N-sulfamoylpyrrole-2-carboxylates (NSPCs) which are potent inhibitors of clinically relevant B1 subclass MBLs, including NDM-1. Crystallography reveals that the N-sulfamoyl NH2 group displaces the dizinc bridging hydroxide/water of the B1 MBLs. Comparison of crystal structures of an NSPC and taniborbactam (VRNX-5133), presently in Phase III clinical trials, shows similar binding modes for the NSPC and the cyclic boronate ring systems. The presence of an NSPC restores meropenem efficacy in clinically derived E. coli and K. pneumoniae blaNDM-1. The results support the potential of NSPCs and related compounds as efficient MBL inhibitors, though further optimization is required for their clinical development.

Highlights

Metallo-β-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of β-lactam antibiotics except monobactams
Related sulfonamide-based inhibitors of metalloenzymes are used therapeutically, e.g. as carbonic anhydrase inhibitors with broad clinical utility.[23−25] The N-sulfamoylpyrrole compounds are of mechanistic interest because the binding mode of some classes of potent βlactamase inhibitors can mimic that of substrates or tetrahedral intermediates.[26]
We targeted the synthesis of NSPC 6a, which has a parafluorophenyl substitution at its C3 position, because this substituent has been identified as being preferred in a related series of published pyrrole inhibitors (Scheme 1).[33,34]

Summary

Introduction

Metallo-β-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of β-lactam antibiotics except monobactams. Related sulfonamide-based inhibitors of metalloenzymes are used therapeutically, e.g. as carbonic anhydrase inhibitors with broad clinical utility.[23−25] The N-sulfamoylpyrrole compounds are of mechanistic interest because the (initial) binding mode of some classes of potent βlactamase inhibitors can mimic that of substrates (e.g., clavulanic acid) or tetrahedral intermediates (boronates).[26] We envisaged that the approximately tetrahedral geometry about the sulfamoyl sulfur[27,28] may mimic the tetrahedral intermediate formed during β-lactam hydrolysis, and the Lewis basicity of the oxygen. We report on the mechanism of action and B1 MBL potencies of N-sulfamoyl-substituted pyrrole-2-carboxylic acids (NSPCs)

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