7AUX

Crystal structure of OXA-48 beta-lactamase in the complex with the inhbitor ID2

Summary for 7AUX

• Entry DOI: 10.2210/pdb7aux/pdb
• Descriptor: Beta-lactamase, CHLORIDE ION, 6-(4-carboxyphenyl)-3-(4-ethylphenyl)-2~{H}-pyrazolo[3,4-b]pyridine-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: class d beta-lactamase, oxa-48, antibiotic, dimer, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 57005.77

Authors

Pochetti, G.,Montanari, R.,Capelli, D.,Garofalo, B.,Ombrato, R. (deposition date: 2020-11-03, release date: 2021-07-21, Last modification date: 2024-01-31)

Primary citation

Garofalo, B.,Prati, F.,Buonfiglio, R.,Coletta, I.,D'Atanasio, N.,Molteni, A.,Carettoni, D.,Wanke, V.,Pochetti, G.,Montanari, R.,Capelli, D.,Milanese, C.,Di Giorgio, F.P.,Ombrato, R.
Discovery of Novel Chemical Series of OXA-48 beta-Lactamase Inhibitors by High-Throughput Screening.
Pharmaceuticals, 14:-, 2021

PubMed Abstract: The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem's activity in ATCC BAA-2523 β-lactam resistant strain. Also, showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs.

PubMed: 34202402
DOI: 10.3390/ph14070612

Experimental method

X-RAY DIFFRACTION (2.05 Å)