Antibiotic resistance is one of the most significant challenges facing global healthcare. Since the 1940s, antibiotics have been used to fight infections, initially with penicillin and subsequently with various deriva...Antibiotic resistance is one of the most significant challenges facing global healthcare. Since the 1940s, antibiotics have been used to fight infections, initially with penicillin and subsequently with various derivatives including cephalosporins, carbapenams and monobactams. A common characteristic of these antibiotics is the four-memberedβ-lactam ring. Alarmingly, in recent years an increasing number of bacteria have become resistant to these antibiotics. A major strategy employed by these pathogens is to use Zn(II)-dependent enzymes, the metallo-β-lactamases (MBLs), which hydrolyse theβ-lactam ring. Clinically useful MBL inhibitors are not yet available. Consequently, MBLs remain a major threat to human health. In this review biochemical properties of MBLs are discussed, focusing in particular on the interactions between the enzymes and the functionally essential metal ions. The precise role(s) of these metal ions is still debated and may differ between different MBLs. However, since they are required for catalysis, their binding site may present an alternative target for inhibitor design.展开更多
Metallo-β-lactamases (MBLs) are a family of Zn2+-dependent enzymes that have contributed strongly to the emergence and spread of antibiotic resistance. Novel members as well as variants of existing members of this fa...Metallo-β-lactamases (MBLs) are a family of Zn2+-dependent enzymes that have contributed strongly to the emergence and spread of antibiotic resistance. Novel members as well as variants of existing members of this family are discovered continuously, compounding their threat to global health care. MBLs are divided into three subgroups, i.e. B1, B2 and B3. The recent discovery of an unusual MBL from Serratia proteamaculans (SPR-1) suggests the presence of an additional subgroup, i.e. B4. A database search reveals that SPR-1 has only one homologue from Cronobacter sakazakii, CSA-1.These two MBLs have a unique active site and may employ a mechanism distinct from other MBLs, but reminiscent of some organophosphate-degrading hydrolases.展开更多
Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzyme...Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzymes, is among the most potent. MBLs are subdivided into three groups (i.e. B1, B2 and B3) with most of the virulence factors belonging to the B1 group. The recent discovery of AIM-1, a B3-type MBL, however, has illustrated the potential health threat of this group of MBLs. Here, we employed a bioinformatics approach to identify and characterize novel B3-type MBLs from Novosphingobium pentaromativorans and Simiduia agarivorans. These enzymes may not yet pose a direct risk to human health, but their structures and function may provide important insight into the design and synthesis of a still elusive universal MBL inhibitor.展开更多
This thesis developed a LC-ESI-TRAP-MS method for twelve β-lactam antibiotics residues in milk.The massspectrometer was operated in the positive ion mode using multiple reaction monitoring.The limit of detection is 1...This thesis developed a LC-ESI-TRAP-MS method for twelve β-lactam antibiotics residues in milk.The massspectrometer was operated in the positive ion mode using multiple reaction monitoring.The limit of detection is 1.0 and 2.0 μg/L.Overall recoveries were between 55.2% and 109.5%.展开更多
β-lactamase,a kind of hydrolase in multi-drug resistant pathogens,can hydrolyzeβ-lactam antibiotics and make these kinds of antibiotics invalid.Small-molecular inhibitors about the enzyme and their mechanism are wid...β-lactamase,a kind of hydrolase in multi-drug resistant pathogens,can hydrolyzeβ-lactam antibiotics and make these kinds of antibiotics invalid.Small-molecular inhibitors about the enzyme and their mechanism are widely investigated but they may result in unavoidable adverse reactions and drug-resistance.Herein,we propose a new therapeutic strategy of Chinese materioherbology,in which herbal medicine or traditional Chinese medicinal herbs can be employed as biological functional materials or refreshed/excited by means of materialogy.Nat-ural tea nanoclusters(TNCs)were extracted from tea to inhibitβ-lactamase.Different from the mechanism of small-molecular inhibitors inhibiting enzymes by binding to the corresponding active sites,the TNCs as a cap cover the protein pocket and create a spatial barrier between the active sites and antibiotics,which was named“capping-pocket”effect.TNCs were combined with amoxicillin sodium(Amo)to treat the methicillin-resistant Staphylococcus aureus(MRSA)pneumonia in mice.This combinatorial therapy remarkably outperforms antibiotic monotherapy in reducing MRSA infections and the associated inflammation in mice.The therapeutic strategy exhibited excellent biosafety,without any side effects,even in piglets.Hence,TNCs have great clinical value in potentiatingβ-lactam antibiotic activity for combatting multi-drug resistant pathogen infections and the"pocket capping"effect can guide the design of new enzyme inhibitors in near future.展开更多
基金N.M.thanks the Science Foundation Ireland(SFI)for financial support in form of a President of Ireland Young Researcher Award(PIYRA) G.S.acknowledges the award of a Future Fellowship from the Australian Research Council(FT120100694)and is grateful to the National Health and Medical Research Council of Australia for funding.
文摘Antibiotic resistance is one of the most significant challenges facing global healthcare. Since the 1940s, antibiotics have been used to fight infections, initially with penicillin and subsequently with various derivatives including cephalosporins, carbapenams and monobactams. A common characteristic of these antibiotics is the four-memberedβ-lactam ring. Alarmingly, in recent years an increasing number of bacteria have become resistant to these antibiotics. A major strategy employed by these pathogens is to use Zn(II)-dependent enzymes, the metallo-β-lactamases (MBLs), which hydrolyse theβ-lactam ring. Clinically useful MBL inhibitors are not yet available. Consequently, MBLs remain a major threat to human health. In this review biochemical properties of MBLs are discussed, focusing in particular on the interactions between the enzymes and the functionally essential metal ions. The precise role(s) of these metal ions is still debated and may differ between different MBLs. However, since they are required for catalysis, their binding site may present an alternative target for inhibitor design.
基金N.M.thanks the Science Foundation Ireland(SFI)for financial support in the form of a President of Ireland Young Researcher Award(PIYRA)G.S.acknowledges the award of a Future Fellowship from the Australian Research Council(FT120100694)D.O.and G.S.are grateful to the National Health and Medical Research Council of Aus-tralia for funding.
文摘Metallo-β-lactamases (MBLs) are a family of Zn2+-dependent enzymes that have contributed strongly to the emergence and spread of antibiotic resistance. Novel members as well as variants of existing members of this family are discovered continuously, compounding their threat to global health care. MBLs are divided into three subgroups, i.e. B1, B2 and B3. The recent discovery of an unusual MBL from Serratia proteamaculans (SPR-1) suggests the presence of an additional subgroup, i.e. B4. A database search reveals that SPR-1 has only one homologue from Cronobacter sakazakii, CSA-1.These two MBLs have a unique active site and may employ a mechanism distinct from other MBLs, but reminiscent of some organophosphate-degrading hydrolases.
基金N.M.thanks the Science Foundation Ireland(SFI)for financial support in form of a President of Ireland Young Researcher Award(PIYRA)G.S.acknowledges the award of a Future Fellowship from the Australian Research Council(FT120100694)is grateful to the National Health and Medical Research Council of Australia for funding.
文摘Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzymes, is among the most potent. MBLs are subdivided into three groups (i.e. B1, B2 and B3) with most of the virulence factors belonging to the B1 group. The recent discovery of AIM-1, a B3-type MBL, however, has illustrated the potential health threat of this group of MBLs. Here, we employed a bioinformatics approach to identify and characterize novel B3-type MBLs from Novosphingobium pentaromativorans and Simiduia agarivorans. These enzymes may not yet pose a direct risk to human health, but their structures and function may provide important insight into the design and synthesis of a still elusive universal MBL inhibitor.
文摘This thesis developed a LC-ESI-TRAP-MS method for twelve β-lactam antibiotics residues in milk.The massspectrometer was operated in the positive ion mode using multiple reaction monitoring.The limit of detection is 1.0 and 2.0 μg/L.Overall recoveries were between 55.2% and 109.5%.
基金This work was jointly supported by the China National Funds for Distinguished Young Scientists(Grant No.51925104)National Natural Science Foundation of China(Grants No.51871162 and 52173251)+2 种基金RGC/NSFC(Grant No.N_HKU725-1616)Hong Kong ITC(Grants No.ITS/287/17,GHX/002/14SZ)Health and Medical Research Fund(Grant No.03142446).
文摘β-lactamase,a kind of hydrolase in multi-drug resistant pathogens,can hydrolyzeβ-lactam antibiotics and make these kinds of antibiotics invalid.Small-molecular inhibitors about the enzyme and their mechanism are widely investigated but they may result in unavoidable adverse reactions and drug-resistance.Herein,we propose a new therapeutic strategy of Chinese materioherbology,in which herbal medicine or traditional Chinese medicinal herbs can be employed as biological functional materials or refreshed/excited by means of materialogy.Nat-ural tea nanoclusters(TNCs)were extracted from tea to inhibitβ-lactamase.Different from the mechanism of small-molecular inhibitors inhibiting enzymes by binding to the corresponding active sites,the TNCs as a cap cover the protein pocket and create a spatial barrier between the active sites and antibiotics,which was named“capping-pocket”effect.TNCs were combined with amoxicillin sodium(Amo)to treat the methicillin-resistant Staphylococcus aureus(MRSA)pneumonia in mice.This combinatorial therapy remarkably outperforms antibiotic monotherapy in reducing MRSA infections and the associated inflammation in mice.The therapeutic strategy exhibited excellent biosafety,without any side effects,even in piglets.Hence,TNCs have great clinical value in potentiatingβ-lactam antibiotic activity for combatting multi-drug resistant pathogen infections and the"pocket capping"effect can guide the design of new enzyme inhibitors in near future.
