Structural and Kinetic Basis for the Rational Design of Next-Generation β‑Lactamase Inhibitors
Shuang Chen, Muchen Yu, Manming Xu, Sergio Decherchi, Magdalena A. Taracila, Andrea M. Hujer, Christopher R. Bethel, Robert A. Bonomo, Shozeb Haider
TL;DR
This study explores how boron-based inhibitors bind to β-lactamase enzymes, revealing key molecular interactions that could guide the design of better antibiotics.
Contribution
The study identifies conserved binding motifs and a shared anchoring point in β-lactamases, offering new design principles for inhibitors.
Findings
Three binding pathways were identified, guided by hydrophobic motifs and a conserved arginine anchor.
R349 is suggested as a shared anchoring point across serine β-lactamases.
Hydrogen-bonding interactions delay productive binding by stabilizing nonproductive conformations.
Abstract
The global spread of β-lactamase-mediated resistance poses a threat to β-lactam antibiotics. Boron-based β-lactamase inhibitors (BLIs) represent a promising class of reversible covalent inhibitors, yet the molecular basis of their recognition and dissociation remains poorly understood. Using Pseudomonas-derived cephalosporinase-3 (PDC-3) as a model, we employed enhanced sampling strategies with machine learning and steady-state kinetic assays to investigate the binding and unbinding dynamics of LP06, a boronate BLI. We identify three binding pathways, governed by hydrophobic recognition motifs and a conserved arginine anchor that together steer the ligand toward the precovalent state. Sequence alignment of nearly 7000 class C β-lactamases supports the conservation of these determinants, and structural analyses suggest that R349 may act as a shared anchoring point across serine…
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Taxonomy
TopicsAntibiotic Resistance in Bacteria · Synthesis of β-Lactam Compounds · Antibiotics Pharmacokinetics and Efficacy