Inhibition Research Of Antibiotic Resistance Targeting Protein Metallo-?-lactamases And Drug-resistant Bacteria

?-Lactam antibiotics are one kind of the most important and frequently used antimicrobial agents. The overuse of antibiotics in the clinical setting has resulted in antibiotic resistance. One of the bacteria resistance mechanisms for ?-lactam antibiotics is to produce ?-lactamases, which hydrolyze the P-lactam rings of ?-lactam containing antibiotics. Metallo-?-lactamases ?M?Ls? hydrolyze almost all ?-lactam antibiotics. However, there is no M?Ls inhibitors for clinic purpers to date. The most effective method against antibiotic resistance is to develop the M?L inhibitors. Based on this idea, we carried out the following research works.1. Thirteen new amino acid thioesters were developed by replacement of the substituents on the N-terminus and the amino acid side chain of the thioesters. Biological activity assays indicated that twelve of them are very potent inhibitors of L1, with an IC₅₀ value range of 0.02-1.08?M. Analysis of structure-activity relationship revealed that the big hydrophobic substituents on N-terminus and polar groupsat amino acid side chain improve inhibitory activity of the thioesters. All these inhibitors, except one compound, were able to improve antibacterial activity of ?-lactam antibiotics against E. coli BL21?DE3? cells producing L1, resulting in 4-to 8-fold reduction in MIC values. Docking studies revealed that the big hydrophobic group on N-terminal resulted in a change of binding mode between inhibitor and the enzyme.2. Five selenium compounds were designed and synthesised, four of them effectively inhibit CcrA and NDM-1 with an IC₅₀ value lower than 0.1 ?M. Antibacterial experiments indicated that two of them showed synergistic effect against four drug-resistant bacteria with MIC value decreased more than 256-fold.3. Fourteen azolylthioacetamides were designed, synthesised and characterized by 1H and 13C NMR and confirmed by MS. The inhibition study indicated that the most azolylthioacetamides inhibited NDM-1, and one of them showed the best activity with an IC₅₀ value of 3.80 ?M.