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
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.
