9QP7

APH(2'')-IVa with an inhibitor

This is a non-PDB format compatible entry.

Summary for 9QP7

• Entry DOI: 10.2210/pdb9qp7/pdb
• Descriptor: APH(2'')-Id, DIMETHYL SULFOXIDE, (2~{R})-3-[4-(5-chloranyl-1~{H}-pyrrolo[2,3-b]pyridin-4-yl)-1,2,3-triazol-1-yl]propane-1,2-diol, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, enzyme, antibiotic
• Biological source: Enterococcus casseliflavus
• Total number of polymer chains: 2
• Total formula weight: 76249.76

Authors

Guichou, J.F.,Gelin, M.,Tomaszczyk, M.,Kowalewski, J.,Lionne, C. (deposition date: 2025-03-26, release date: 2026-02-11)

Primary citation

Buffa, V.,Kowalewski, J.,Qi, G.,Deutscher, R.,Cica, M.,Richardoz, M.,Tomaszczyk, M.,Kramer, A.,Knapp, S.,Dunyach-Remy, C.,Rox, K.,Guichou, J.F.,Lionne, C.,Hausch, F.
Targeting bacterial kinases as a strategy to counteract antibiotic resistance.
Commun Chem, 8:390-390, 2025

PubMed Abstract: Antibiotic resistance is rapidly emerging as one of the most critical health threats, with resistant microorganisms progressively diminishing the effectiveness of established antibiotics. As a result, the development of therapeutic approaches that effectively target resistant pathogens is of utmost importance. In this study, we developed inhibitors for APH(2")-IVa, a bacterial kinase conveying resistance to aminoglycoside antibiotics. Starting from a hit of a fragment-based screening, we explored the inhibitory motif by structure-based design, ultimately leading to a series of triazole analogues. Advanced analogues displayed promising ADME properties, emerging selectivity vs a panel of human kinases, permeability in both Gram-positive and Gram-negative bacteria, and a moderate antibiotic efficacy for clinical strains of P. aeruginosa. Taken together, our results suggest inhibition of bacterial kinases could be a promising option to reinstall the efficacy of aminoglycoside antibiotics.

PubMed: 41345223
DOI: 10.1038/s42004-025-01794-7

Experimental method

X-RAY DIFFRACTION (2.5 Å)