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

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

Engineering (Jul 2024)

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

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

Affiliations

Zhuoren Ling: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK; Corresponding author.
Alistair James Macdonald Farley: Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UK
Aditya Lankapalli: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Yanfang Zhang: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Shonnette Premchand-Branker: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Kate Cook: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Andrei Baran: Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia
Charlotte Gray-Hammerton: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Claudia Orbegozo Rubio: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Edgars Suna: Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia
Jordan Mathias: Department of Medical Microbiology, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
Jürgen Brem: Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UK; Enzymology and Applied Biocatalysis Research Center, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, Cluj-Napoca 400028, Romania
Kirsty Sands: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Maria Nieto-Rosado: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Maria Mykolaivna Trush: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Nadira Naznin Rakhi: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Willames Martins: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Yuqing Zhou: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK
Christopher Joseph Schofield: Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UK
Timothy Walsh: Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK

Journal volume & issue: Vol. 38
pp. 124 – 132

Abstract

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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.

Published in Engineering

ISSN: 2095-8099 (Print); 2096-0026 (Online)
Publisher: Elsevier
Country of publisher: China
LCC subjects: Technology: Engineering (General). Civil engineering (General)
Website: http://www.journals.elsevier.com/engineering

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