Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain.
Servicio de Microbiología do Complexo Hospitalario Universitario da Coruña (CHUAC), Instituto de Investigación Biomédica da Coruña (INIBIC), Xubias de Arriba, 84, 15006 A Coruña, Spain.
J Med Chem. 2020 Apr 9;63(7):3737-3755. doi: 10.1021/acs.jmedchem.0c00127. Epub 2020 Mar 31.
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.
基于 6-(芳基)亚甲基青霉素的砜类化合物能够重新利用β-内酰胺抗生素的活性，这些抗生素可以与携带碳青霉烯水解酶 D 类β-内酰胺酶（OXA-23、OXA-24/40 和 OXA-48）的细菌，以及 A 类（TEM-1、CTX-M-2）和 C 类（CMY-2、DHA-1）酶的细菌结合。研究报道了亚胺培南/和亚胺培南/与 OXA-23 和 OXA-24/40 碳青霉烯酶产生菌（1μg/mL）的组合几乎完全恢复了抗生素的疗效，并且对 OXA-48 碳青霉烯酶产生菌（4μg/mL）也有很好的效果。化合物-与头孢他啶和氨苄西林的组合在携带 C 类（CMY-2 和 DHA-1）和 A 类（TEM-1 和 CTX-M-2）β-内酰胺酶的菌株中也能有效地恢复抗生素的疗效。与 OXA-24/40 酶的动力学和抑制研究、蛋白质质谱分析和对接研究使我们能够深入了解抑制机制和实验观察到的配体之间的差异。
