Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1(NDM-1)are a type of newly discovered antibioticresistant bacteria.The rapid pandemic spread of NDM-1 bacteri...Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1(NDM-1)are a type of newly discovered antibioticresistant bacteria.The rapid pandemic spread of NDM-1 bacteria worldwide(spreading to India,Pakistan,Europe,America,and Chinese Taiwan)in less than 2 months characterizes these microbes as a potentially major global health problem.The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations.The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics,allowing the bacteria to escape the action of antibiotics.Although the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues,the precise molecular characteristics and mechanism of action of NDM-1 have not been clarified.Here,we report the threedimensional structure of NDM-1 with two catalytic zinc ions in its active site.Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity.The unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases(MBLs)and implicate its role in wide spectrum drug resistance.We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria.Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.30870486 and 30730022)the National Major Projects(Grant Nos.2009ZX10004-804,2009ZX09311-001 and 2009ZX10004-304)the National Basic Research Program(973 Program)(Grant Nos.2011CB915501 and 2011CB910304).
文摘Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1(NDM-1)are a type of newly discovered antibioticresistant bacteria.The rapid pandemic spread of NDM-1 bacteria worldwide(spreading to India,Pakistan,Europe,America,and Chinese Taiwan)in less than 2 months characterizes these microbes as a potentially major global health problem.The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations.The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics,allowing the bacteria to escape the action of antibiotics.Although the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues,the precise molecular characteristics and mechanism of action of NDM-1 have not been clarified.Here,we report the threedimensional structure of NDM-1 with two catalytic zinc ions in its active site.Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity.The unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases(MBLs)and implicate its role in wide spectrum drug resistance.We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria.Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.
