6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens.

The ability of 6-(aryl)methylidene penicillin-based sulfones - 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/ and imipenem/ restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing strains (1 μg mL) and also provided good results for OXA-48 carbapenemase-producing strains (4 μg mL). Compounds - in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in 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.