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6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-31 , DOI: 10.1021/acs.jmedchem.0c00127 Diana Rodríguez 1 , María Maneiro 1 , Juan C Vázquez-Ucha 2 , Alejandro Beceiro 2 , Concepción González-Bello 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-31 , DOI: 10.1021/acs.jmedchem.0c00127 Diana Rodríguez 1 , María Maneiro 1 , Juan C Vázquez-Ucha 2 , Alejandro Beceiro 2 , Concepción González-Bello 1
Affiliation
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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.
中文翻译：
基于6-芳基亚甲基青霉素的砜类抑制剂，可重新利用优先病原体中的抗生素效率。
的6-能力（芳基）亚甲基系青霉素砜1 - 7重新利用β内酰胺与碳青霉烯类携带水解d类β内酰胺酶（OXA-23细菌种类的抗生素活性，OXA-24/40和OXA-48 ），以及A类（TEM-1，CTX-M-2）和C类（CMY-2，DHA-1）酶。亚胺培南/ 3和亚胺培南/ 4的组合几乎完全恢复了产生OXA-23和OXA-24 / 40碳青霉烯酶的鲍曼不动杆菌菌株（1μgmL –1）的抗生素功效，也为OXA-48碳青霉烯酶-产生肺炎克雷伯菌菌株（4μgmL –1）。化合物2 – 6与头孢他啶和氨苄西林联用还分别有效地恢复了携带C类（CMY-2和DHA-1）和A类（TEM-1和CTX-M-2）β-内酰胺酶的大肠杆菌的抗生素功效。使用OXA-24 / 40酶进行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理以及配体之间的实验观察差异。
更新日期：2020-04-01
中文翻译：
基于6-芳基亚甲基青霉素的砜类抑制剂，可重新利用优先病原体中的抗生素效率。
的6-能力（芳基）亚甲基系青霉素砜1 - 7重新利用β内酰胺与碳青霉烯类携带水解d类β内酰胺酶（OXA-23细菌种类的抗生素活性，OXA-24/40和OXA-48 ），以及A类（TEM-1，CTX-M-2）和C类（CMY-2，DHA-1）酶。亚胺培南/ 3和亚胺培南/ 4的组合几乎完全恢复了产生OXA-23和OXA-24 / 40碳青霉烯酶的鲍曼不动杆菌菌株（1μgmL –1）的抗生素功效，也为OXA-48碳青霉烯酶-产生肺炎克雷伯菌菌株（4μgmL –1）。化合物2 – 6与头孢他啶和氨苄西林联用还分别有效地恢复了携带C类（CMY-2和DHA-1）和A类（TEM-1和CTX-M-2）β-内酰胺酶的大肠杆菌的抗生素功效。使用OXA-24 / 40酶进行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理以及配体之间的实验观察差异。
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