| The overuse of antibiotics in the clinical setting has resulted in a large amount of drug-resistant bacteria emerging. These bacteria often express metallo-β-lactamases (MβLs), which could hydrolyze the β-lactam ring of β-lactam antibiotics. In recent years, MβLs have been an increeasing threat, especially New Delhi metallo-β-lactamase (NDM-1) could hydrolyse aomost all β-lactam antibiotics including penicillins, cephalosporins and carbapenems. However, there has never been any useful inhibitors in clinics today. It is essential to develop effective and broad-spectrum inhibitors of MβLs. Based on this target, we carried out the following research work:1.20 azolylthioacetamides were synthesized by introducing various carboxy groups and a-chloroacetamides into the two sides of triazole ring. They were tested as inhibitors of representative enzymes from the distinct MβL subclasses. The inhibition study indicated nine azolylthioacetamides specifically inhibited ImiS, while 1c showed the best activity with IC50 value of 0.07 μM, Ki value of 1.2 μM. Docking studies revealed that the aromatic carboxyl at the triazole ring of azolylthioacetamide improved inhibitory activity of the inhibitors against ImiS, but an aliphatic carboxyl did not. Antibacterial experiments indicated several azolylthioacetamides showed synergistic effect against pseudomonas aeruginosa and E. coli BL21(DE3) cells producing CcrA or ImiS with MIC value decreased 2-32-fold.2. We designed the synthetic route of monocyclic β-phosphoramide as potential inhibitors of metallo-β-lactamases based on the characteristic structure of β-lactam antibiotics, and acquired target compound through a 8-step protocol finally. The inhibitory activity assay indicated it could effectively inhibit CcrA of B1 subclass, exhibiting 82% inhibition rate with a concentration of 5 uM.We successfully designed and synthesized azolylthioacetamides and monocyclic β-phosphoramide, which provided a new approach to develop novel inhibitors of MβLs. |
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