A new type of lactamase inhibitor: averbactam

Avibactam sodium is a covalent, reversible β - lactamase inhibitor,For serine as the active site β - lactamase are designed to overcome bacterial production! The potential of β - lactamase to cause drug resistance problems.,1.Drug resistance mechanism of Enterobacteriaceae

1,Xdr-gnb is a kind of gram-negative bacilli which is not sensitive to almost all antibiotics except 1-2 kinds of antibiotics (polymyxin and tigecycline). Extensively drug resistant Enterobacteriaceae (XDR) mainly occurs in Klebsiella pneumoniae. Its phenotype is mainly caused by carbapenemase, belonging to! Lactamases. According to amino acid and nucleotide sequences, β - lactamases can be divided into serine β - lactamases, including amblera group (ESBL and KPC enzyme), plasmid or chromosome mediated amblerc group (mainly AmpC enzyme), amblerd group (oxa-48, OXA-23) and metalloenzyme amblerb group. The drug-resistant agents of XDR include carbapenemase (KPC), simultaneous production of ESBL and / or AmpC by some strains, overexpression of efflux pump and mutation of porin.

2,Advantages of avibatan

There are three kinds of β - lactamase inhibitors on the market, which are clavulanic acid, sulbactam and tazobactam. When combined with β - lactamase antibiotics, these inhibitors can irreversibly bind to β - lactamase to protect antibiotic activity and avoid its inactivation. These inhibitors mainly inhibit the β - lactamases in amblera group, but they have no effect on other β - lactamases. A new type of β - lactamase inhibitor, averbactam, not only has a broad inhibition spectrum, but also can inhibit β - lactamases such as ESBL, KPC, AmpC and oxa-48, and the inhibition effect is stronger. Reports show that averbactam only needs 1 ~ 5 to inhibit a β - lactamase, while tazobactam and clavulanic acid need 55 ~ 21 Four.

3,The mechanism of action of averbactam

Averbactam belongs to diazabicyclodioctyl ketone, and the structure of its key region is similar to that of β - lactams. Classical β - lactamase inhibitors are all β - lactamases. Their mechanism of action is the formation of non covalent Michaelis complex with β - lactamase, the nucleophilic attack of serine on amide bond, the ring opening of β - lactamase, the inactivation of β - lactamase by rearrangement, and the destruction of its own structure. And avibatan and! The nucleophilic reaction of serine of lactamase results in the formation of covalent compound and the formation of Enzyme Inhibitor complex. This complex is in the form of enzyme inhibition and does not undergo hydrolysis. After cyclization, the lactamase is formed and then averbactam is obtained. In this process, nucleophilic reaction leads to the rate of ring opening much faster than cyclization, so that β - lactamase is basically in the inhibition state. Because its structure can be recovered by reverse reaction, averbactam plays a long-term inhibitory role.