6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens
- 20 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (7), 3737-3755
- https://doi.org/10.1021/acs.jmedchem.0c00127
Abstract
The ability of 6-(aryl)methylidene penicillin-based sulfones 1−7 to repurpose β-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D β-lactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 µg mL−1), and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 µg mL−1). Compounds 2−6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) β-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.Keywords
Funding Information
- European Regional Development Fund
- Secretar?a de Estado de Investigaci?n, Desarrollo e Innovaci?n (SAF2016-75638-R)
- Xunta de Galicia (ED431B 2018/04, ED431G 2019/03)
- Instituto de Salud Carlos III (CP13/00226, PI14/00059, PI17/01482, PI17/1484)
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