Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening.

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 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 μM) inhibited OXA-48 via a reversible and competitive mechanism o

SUBMITTER: Garofalo B 

PROVIDER: S-EPMC8308845 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature