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

[Display omitted] This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteri...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:Engineering (Beijing, China) Ročník 38; číslo 7; s. 124 - 132
Hlavní autoři: Ling, Zhuoren, Farley, Alistair James Macdonald, Lankapalli, Aditya, Zhang, Yanfang, Premchand-Branker, Shonnette, Cook, Kate, Baran, Andrei, Gray-Hammerton, Charlotte, Orbegozo Rubio, Claudia, Suna, Edgars, Mathias, Jordan, Brem, Jürgen, Sands, Kirsty, Nieto-Rosado, Maria, Trush, Maria Mykolaivna, Rakhi, Nadira Naznin, Martins, Willames, Zhou, Yuqing, Schofield, Christopher Joseph, Walsh, Timothy
Médium: Journal Article
Jazyk:angličtina
Vydáno: China Elsevier Ltd 01.07.2024
Enzymology and Applied Biocatalysis Research Center,Faculty of Chemistry and Chemical Engineering,Babes-Bolyai University,Cluj-Napoca 400028,Romania
Department of Biology & Ineos Oxford Institute for Antimicrobial Research,University of Oxford,Oxford OX1 3RE,UK%Chemistry Research Laboratory,Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research,University of Oxford,Oxford OX1 3TA,UK%Latvian Institute of Organic Synthesis,Riga LV-1006,Latvia%Department of Medical Microbiology,Division of Infection and Immunity,School of Medicine,Cardiff University,Cardiff CF14 4XN,UK%Chemistry Research Laboratory,Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research,University of Oxford,Oxford OX1 3TA,UK
Higher Education Press
Elsevier
Témata:
Antimicrobial resistance
Avibactam
Carbapenemase
Meropenem
Metallo/serine-β-lactamase inhibitor
Research Natural Medicine
Carbapenemase
Avibactam
Meropenem
Antimicrobial resistance
Metallo/serine-β-lactamase inhibitor
ISSN:2095-8099, 2096-0026
On-line přístup:Získat plný text
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí:[Display omitted] This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-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-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (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 β-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 carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2095-8099
2096-0026
DOI:10.1016/j.eng.2024.02.010