Same Substitutions, Opposite Residence Times: Target-Dependent Kinetic Inversion of Diazabicyclooctane 𝛽-Lactamase Inhibitors
- 1Faculty of Medicine
- 2Mansoura University
- 3Faculty of Pharmacy
Abstract
Reversible covalent inhibitors are governed by both formation and breakdown of the covalent complex, yet matched medicinal-chemistry modifications are often interpreted through affinity or potency alone. We performed an original quantitative reanalysis of published experimental kinetics and corresponding covalent crystal structures for four diazabicyclooctane (DBO) inhibitors—avibactam, FPI-1465, FPI-1523, and FPI-1602—against CTX-M-15 and OXA-48. Relative to avibactam, all three C2-modified analogues showed lower 𝑘2/𝐾𝑖 in both enzymes, but their effects on dissociation reversed sign between targets. FPI-1465, FPI-1523, and FPI-1602 dissociated 3.86-, 3.38-, and 4.91-fold more slowly from CTX-M-15, whereas they dissociated 68.8-, 3.12-, and 2.73-fold more rapidly from OXA-48. The corresponding cross-target interactions were 265.5-, 10.5-, and 13.4-fold. Eyring transformation mapped these effects to shifts in the reverse activation barrier of +0.72 to +0.94 kcal mol−1 in CTX-M-15 versus −0.59 to −2.51 kcal mol−1 in OXA-48. Static oxyanion-hole geometry did not encode the OXA-48 ranking: mean donor–carbonyl-oxygen distances changed by only 0.002–0.065 Å relative to avibactam despite 2.7–68.8-fold changes in 𝑘off. These findings identify a replicated target-dependent residence-time inversion and demonstrate that forward and reverse structure–kinetic relationships can diverge within a matched reversible-covalent series. Conformational ensembles and distributed electrostatics emerge as specific prospective mechanisms, but are not inferred as causal from the present static-structure analysis.
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BibTeX
@misc{fouda2026same,
title = {{Same Substitutions, Opposite Residence Times: Target-Dependent Kinetic Inversion of Diazabicyclooctane 𝛽-Lactamase Inhibitors}},
author = {Abdel-Motaal M. Fouda and Dina A. Fouda},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008332/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008332/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Same Substitutions, Opposite Residence Times: Target-Dependent Kinetic Inversion of Diazabicyclooctane 𝛽-Lactamase Inhibitors
AU - Abdel-Motaal M. Fouda
AU - Dina A. Fouda
PY - 2026
DA - 2026/09/04
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008332/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008332/v1
AB - Reversible covalent inhibitors are governed by both formation and breakdown of the covalent complex, yet matched medicinal-chemistry modifications are often interpreted through affinity or potency alone. We performed an original quantitative reanalysis of published experimental kinetics and corresponding covalent crystal structures for four diazabicyclooctane (DBO) inhibitors—avibactam, FPI-1465, FPI-1523, and FPI-1602—against CTX-M-15 and OXA-48. Relative to avibactam, all three C2-modified analogues showed lower 𝑘2/𝐾𝑖 in both enzymes, but their effects on dissociation reversed sign between targets. FPI-1465, FPI-1523, and FPI-1602 dissociated 3.86-, 3.38-, and 4.91-fold more slowly from CTX-M-15, whereas they dissociated 68.8-, 3.12-, and 2.73-fold more rapidly from OXA-48. The corresponding cross-target interactions were 265.5-, 10.5-, and 13.4-fold. Eyring transformation mapped these effects to shifts in the reverse activation barrier of +0.72 to +0.94 kcal mol−1 in CTX-M-15 versus −0.59 to −2.51 kcal mol−1 in OXA-48. Static oxyanion-hole geometry did not encode the OXA-48 ranking: mean donor–carbonyl-oxygen distances changed by only 0.002–0.065 Å relative to avibactam despite 2.7–68.8-fold changes in 𝑘off. These findings identify a replicated target-dependent residence-time inversion and demonstrate that forward and reverse structure–kinetic relationships can diverge within a matched reversible-covalent series. Conformational ensembles and distributed electrostatics emerge as specific prospective mechanisms, but are not inferred as causal from the present static-structure analysis.
ER -