9QOL

APH(2'')-IVa with a fragment

Summary for 9QOL

• Entry DOI: 10.2210/pdb9qol/pdb
• Related: 9QMR
• Descriptor: APH(2'')-Id, 5-fluoro-1H-pyrrolo[2,3-b]pyridine (3 entities in total)
• Functional Keywords: inhibitor, complex, enzyme, antibiotic
• Biological source: Enterococcus casseliflavus
• Total number of polymer chains: 2
• Total formula weight: 75465.79

Authors

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

Primary citation

Kowalewski, J.,Deutscher, R.,Richardoz, M.,Tomaszczyk, M.,Gelin, M.,Labesse, G.,Hausch, F.,Wright, G.D.,Dunyach-Remy, C.,Guichou, J.F.,Lionne, C.
Fragment-based drug design of a bacterial kinase inhibitor capable of increasing the antibiotic sensitivity of clinical isolates.
Commun Chem, 8:417-417, 2025

PubMed Abstract: According to the World Health Organization (WHO), antimicrobial resistance is a serious global health issue. Overcoming antibiotic resistance involves several strategies, including the inhibition of resistance mechanisms. Among the various resistance mechanisms, aminoglycoside phosphotransferases (APHs) catalyze the transfer of the γ-phosphate from a nucleotide donor to various aminoglycosides, leading to their inactivation. In this work, using a fragment-based drug design (FBDD) approach, we have identified and characterized a promising APH inhibitor capable of increasing the sensitivity of Pseudomonas aeruginosa and Staphylococcus aureus resistant to aminoglycosides. It is therefore a good candidate for the future development of APH inhibitors to be prescribed in combination with aminoglycosides. This molecule is a competitive inhibitor of adenosine 5'-triphosphate (ATP), the phosphate donor of APHs. Further studies are required to optimize this molecule to improve its specificity for APHs and its bioavailability in bacteria.

PubMed: 41310159
DOI: 10.1038/s42004-025-01795-6

Experimental method

X-RAY DIFFRACTION (2.13 Å)