Inhibition Studies Of Antibiotics Resistant Target Protein M?Ls

Metallo-?-lactamases (M?Ls)-mediated superbugs can neutralize almost all the antibiotics.Both the World Health Organization (WHO) and academia are focused on the inhibition studies of M?Ls and monitoring the drug-resistant bacteria secreting M?Ls. Inhibition studies of antibiotic resistant target protein M?Ls are extremely important for human health,economic and social development, and academic innovation. This paper has carried out the following work:N-substituted carbamylmethyl mercaptoacetate thioether were successfully constructed as a molecular structure of specific inhibitory activity against M?L L1,and sixteen derivatives were synthesized and developed with characterized by 1H, 13C NMR and confirmed by MS.All the obtained mercaptoacetate thioethers have inhibitory activity against seven M?Ls divided into three subclasses; while specific and mixed-type inhibit L1, and the most potent inhibitors with 97% inhibition in the concentration of 100 ?M and an IC50 value of 0.41 ?M.Structure-activity relationship studies have indicated that compounds with electron-donating aromatic groups showed better inhibitory activity against L1, and the electron-donating group in para position of the phenyl exhibited higher inhibitory activity than in ortho position. Isothermal microcalorimetry titration studies corroborate these compounds inhibiting efficacy. Cell toxicity experiments showed that mercaptoacetate thioether derivatives are nontoxic compounds in the determination concentration range. Docking studies suggest that the inhibitor molecules bonding with the two Zn(?) ions in the active site of L1, and forming hydrogen bonds with amino acid residues Ser221 and Tyr32.Design and synthesize eighteen azo1yVUioaceamides derivatives,Uharacterized by 1H,13C NMR and confirmed by MS. Structure-activity relationship study indicated that the amide combined with aliphatic group would weaken the inhibitory activity against ImiS, while the triazole combined with heteroaromatic, no inhibiting effect were observed. This was further evidence that the azolythioacetamide contains two benzene rings could inhibit ImiS better.It is the first time to discover the DNA nanostructure can inhibit M?Ls. Enzyme Kinetics evaluation found that DNA nanostructure have good inhibitory activity against NDM-1 and ImiS, the values of IC50 are 3.32, 11.76 nM! The thermodynamic confirmed the efficacy of DNA nanostructure, and the interaction between DNA nanostructure and NDM-1 also observed by the atomic force microscopy imaging techniques. Undoubtedly, the discovery of interaction between DNA nanostructure and NDM-1 will open up a new study field.