| Since the advent of penicillin in 1928,the ability of humans to resist bacterial infections has been greatly enhanced,leading to the birth of the antibiotic family.As a mainstay of bacterial infection treatment,antibiotics have saved countless lives,and the development of antibiotics is still one of the most important advances in modern medicine.There are four main types of antibiotics in clinical: Penicillin,cephalosporin,carbapenems and monocyclic ?-lactam,The common structural feature of these compounds is that they all have a highly active beta-lactam ring.the reason why Beta-lactam antibiotics have antibacterial activity is that it can block the synthesis of bacterial cell walls.The main component of bacterial cell wall is peptidoglycan.It is a combination of n-acetylcytophosphoric acid and n-acetylglucosamine through the beta-1,4 glycosidic bond,then interwoven into a "reticular" structure through a short peptide tail.Penicillin binding proteins(PBPs)belong to the type of membrane protein on the bacterial cell size film,which is mainly distributed on the cell surface of the gram-negative and gram-positive bacteria.It can catalyze the polymerization and crosslinking of peptides,and its functions include the end reaction,morphological maintenance and adjustment of the biosynthesis of bacterial peptides.The structure of the beta-lactam antibiotic is very similar to that of D-propionyl-D-alanine at the tail end of peptide polysaccharide.When both exist,they compete with each other for the activity center of peptides.Moreover,the affinity of beta-lactam antibiotics is higher than that of d-propionyl-d-alanine,the carbonyl group on its beta-lactam ring can be covalent bonded with the serine hydroxyl group at the active site of the bacterial PBPs,As a result,PBPs lost normal enzyme activity function,and no peptide bridge was formed between the two peptides,and the cell wall synthesis was blocked.The lack of a complete cell wall eventually leads to the death of the bacteria and thus the purpose of sterilization.Since penicillin was used clinically,bacteria have become resistant to antibiotics under pressure to survive.The bacterial resistance to antibiotics,especially the increasingly serious bacterial multidrug resistance,has become a global medical and social problem.There are four main drug resistance mechanisms of bacteria: the first is to produce beta-lactamase,which causes the hydrolysis and inactivation of the antibiotics into the cell.The second is to change the antibiotic binding site,making itdifficult for antibiotics to work.The third is to change the permeability of the outer membrane of the bacteria,making it difficult for antibiotics to enter the cell.The fourth is to use the external pump to remove the antibiotics from the cells.Among them,the production of beta-lactamase,which can hydrolyze the beta-lactam,is the most important and most threatening drug resistance mechanism,and also the research direction of this topic.Beta-lactamases(BLA)are the enzymes that have the activity of hydrolysis of beta-lactamide antibiotics produced by drug-resistant bacteria.Beta-lactamase uses the water molecules of its active center to hydrolyze the acylated compound of the enzyme and antibiotics to obtain the inactivated antibiotics and the active retention enzymes.According to Ambler's molecular structure classification,it can be divided into four categories: A,B,C and D.The active sites of type A,C and D contain serine,while the activity site of B-type enzyme contains metal zinc ions,also known as metal-beta-lactamase.At present,multiple resistance bacteria(MDR)with multiple drug resistance mechanisms and the ability to express multiple types of beta-lactase are the most threatening pathogenic bacteria in clinical practice.In order to overcome the problem of bacterial resistance mediated by beta-lactamase,scientists used beta-lactamase inhibitors and antibiotics as a combination of compound agents.The beta-lactamase inhibitor can bind to beta-lactamase to prevent hydrolysis of beta-lactamide antibiotics,thereby enhancing the antimicrobial activity of beta-lactamide antibiotics.Currently,beta-lactamase inhibitors mainly include clavulanic acid,sulbatan,tazobartan and the recently listed avibatan.The structures of clavicoic acid,sulbatartan and tazobartan are similar to that of penicillin,and their mechanisms are similar.Take clavic acid as an example: the non-covalent Michaelis complex was formed with beta-lactamase.Ser70's hydroxyl attacks the carbonyl of the lactam ring,leading to the opening of the lactam ring and forming acylation products.And then the oxazole open loop,producing the ketone derivatives.Under the action of Ser130,a multistep rearrangement was performed,resulting in the formation of acylated complexes of enzymes and beta-lactamide antibiotics,which caused the enzyme to lose its activity,and the inhibitor itself was decomposed.So clavic acid,sulbatan and tazobatan are all non-reversible inhibitors.Clavicoic acid,sulbatartan and tazobactam have inhibitory effects on most A class of enzymes,and there is no inhibitory effect on B,C and D enzymes.Inaddition,bacteria continuously develop resistance to inhibitors,so it is urgent to develop new broad-spectrum beta-lactamase inhibitors to cope with the increasing number of multidrug-resistant bacteria.Avibactam,which is a diazo-octane compound,has a chemical formula(1R,2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo [3.2.1] octan-2-carboxam-ide.Avibactam is a new type of beta-lactamase inhibitor,which combines with the reversible covalency of the enzyme,and is fundamentally different from that of the classical beta-lactamase inhibitor.Beta-lactamase serine nucleophilic attack on the amide bond of avibactam,open loop and form covalent binding,obtain the enzyme-inhibitor complex,which is the form of enzyme inhibition,and will not be hydrolyzed.And then it forms the lactam ring through the cyclization reaction,back to avibactam.The nucleophilic attack results in the rate of open loop far greater than that of cyclization,which leads to the inhibition of the enzyme.In the process,the structure of avibactam can be recovered by reverse reaction,so its inhibitory effect is long-lasting.Avibactam is more powerful and extensive than clavicoic acid,sulbatartan and tazobactam,it has a strong inhibitory effect on class A and class C beta-lactamase,and also can inhibit partial class D enzymes.What's more,avibactam does not induce the production of beta-lactamase.The activity of antibiotics can be restored or enhanced when avibatan is used in combination with cephalosporin and cephalosporin,and it is well tolerated and no serious adverse events are reported.With avibactam as lead compounds,this paper based on the preliminary structure-activity relationship,design and synthesis of the two types of four-member ring lactam compounds.And 23 compounds,including positive compounds,has carried on the preliminary biological activity evaluation.The inhibitory effects of 23 compounds on Class A TEM-1,Class C AmpC and Class D OXA-23 enzyme were measured,and the inhibitory activity of the target compounds on the enzyme was expressed by the inhibition rate.The results of the activity evaluation showed that,there are eight compounds that have a higher inhibition rate than positive compound for Class D enzyme(OXA-23)at 0.5nM.Due to the fact that there are almost no inhibitor on the class D beta-lactamase,the eight compounds we selected are of great significance to the search for class D beta-lactamase inhibitors. |
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