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Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli

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Abstract

Purpose

Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-β-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate.

Methods

Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L).

Results

Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints.

Conclusion

The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

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Data availability

The data presented in the study are deposited in the NCBI BioProject repository, accession number PRJNA1062769.

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Funding

This work was supported by Qingdao Key Health Discipline Development Fund.

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Authors and Affiliations

  1. Department of Pharmacy, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266042, China

    Xuefeng Zhou, Jianqi Chen, Li Wang & Hai Yang

  2. School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, PR China

    Jiayuan Zhang, Jianqi Chen, Li Wang & Mingming Yu

  3. Department of Statistics, State University of Maringá, Maringá, Paraná, Brazil

    Sherwin K. B. Sy

Authors
  1. Xuefeng Zhou
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Contributions

All authors (i) contributed to the design of the study, acquisition, or analysis of data, (ii) drafted or revised the article for intellectual content, and (iii) approved the final version.

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Correspondence to Sherwin K. B. Sy or Hai Yang.

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Zhou, X., Zhang, J., Chen, J. et al. Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli. Eur J Clin Microbiol Infect Dis (2024). https://doi.org/10.1007/s10096-024-04837-4

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