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Publication Abstract from PubMed

The major cause of bacterial resistance to beta-lactams is the production of hydrolytic beta-lactamase enzymes. Nowadays, the combination of beta-lactam antibiotics with beta-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging beta-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae 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, AC50 = 0.99 muM) 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 Escherichia coli ATCC BAA-2523 beta-lactam resistant strain. Also, ID2 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-beta-lactam BLIs.

Discovery of Novel Chemical Series of OXA-48 beta-Lactamase Inhibitors by High-Throughput Screening.,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 FP, Ombrato R Pharmaceuticals (Basel). 2021 Jun 25;14(7). pii: ph14070612. doi:, 10.3390/ph14070612. PMID:34202402^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.