The Triple Combination of Meropenem,Avibactam,and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers  

作　　者：Zhuoren Ling Alistair James Macdonald Farley Aditya Lankapalli Yanfang Zhang Shonnette Premchand-Branker Kate Cook Andrei Baran Charlotte Gray-Hammerton Claudia Orbegozo Rubio Edgars Suna Jordan Mathias Jürgen Brem Kirsty Sands Maria Nieto-Rosado Maria Mykolaivna Trush Nadira Naznin Rakhi Willames Martins Yuqing Zhou Christopher Joseph Schofield Timothy Walsh 

机构地区：[1]Department of Biology&Ineos Oxford Institute for Antimicrobial Research,University of Oxford,Oxford OX13RE,UK [2]Chemistry Research Laboratory,Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research,University of Oxford,Oxford OX13TA,UK [3]Latvian Institute of Organic Synthesis,Riga LV-1006,Latvia [4]Department of Medical Microbiology,Division of Infection and Immunity,School of Medicine,Cardiff University,Cardiff CF144XN,UK [5]Enzymology and Applied Biocatalysis Research Center,Faculty of Chemistry and Chemical Engineering,Babes-Bolyai University,Cluj-Napoca 400028,Romania

出　　处：《Engineering》2024年第7期124-132,共9页工程（英文）

基　　金：supported by the Ineos Oxford Institute for Antimicrobial Research,the Biotechnology and Biological Sciences Research Council(BB/V003291/1);the WellcomeTrust(106244/Z/14/Z).

摘　　要：This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method.The frequency of resistance(FoR)to MEM combined with InC58 was investigated.Mutants were sequenced and tested for cross resistance,fitness,and the stability of the resistance phenotype.Compared with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(P.aeruginosa)and OXA-23-carrying Acinetobacter baumannii(A.baumannii).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,respectively.The mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.

关 键 词：CARBAPENEMASE Metallo/serine-b-lactamase inhibitor Avibactam MEROPENEM Antimicrobial resistance 

分 类 号：R96[医药卫生—药理学]