Institute of Crystallography - CNR

Discovery of novel chemical series of oxa-48 beta-lactamase inhibitors by high-throughput screening

The major cause of bacterial resistance to ?-lactams is the production of hydrolytic ?-lac-tamase enzymes. Nowadays, the combination of ?-lactam antibiotics with ?-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging ?-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 py-razolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representa-tive of the latter series (ID2, AC50 = 0.99 ?M) 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 ?-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-?-lactam BLIs.

Pharmaceuticals (Basel)
Impact factor
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.