In vitro and in vivo activities of imipenem combined with BLI-489 against class D β-lactamase-producing Acinetobacter baumannii

  • J Antimicrob Chemother. 2021 Jan 19;76(2):451-459. doi: 10.1093/jac/dkaa421.
Yung-Chih Wang  1 ,  Shu-Wei Huang  2  3 ,  Ming-Hsien Chiang  4 ,  I-Ming Lee  5 ,  Shu-Chen Kuo  6 ,  Ya-Sung Yang  1 ,  Chun-Hsiang Chiu  1 ,  Ying-Shih Su  7 ,  Te-Li Chen  8  9 ,  Fu-Der Wang  10  11 ,  Yi-Tzu Lee  2  11
Affiliations
  • 1. Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 2. Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 3. Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
  • 4. Department and Graduate Institute of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
  • 5. Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • 6. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
  • 7. Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan.
  • 8. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 9. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
  • 10. Division of Infectious Diseases, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 11. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
PMID: 33057603 DOI: 10.1093/jac/dkaa421
Abstract

Background: According to our preliminary study, BLI-489 has the potential to inhibit the hydrolysing activity of OXA-51-like β-lactamase produced by carbapenem-resistant Acinetobacter baumannii (CRAb).

Objectives: In the present study, the in vitro and in vivo activities of imipenem combined with BLI-489 against CRAb producing carbapenem-hydrolysing class D β-lactamases (CHDLs), namely OXA-23, OXA-24, OXA-51 and OXA-58, were determined.

Methods: A chequerboard analysis of imipenem and BLI-489 was performed using 57 and 7 clinical CRAb isolates producing different CHDLs and MBLs, respectively. Four representative strains harbouring different CHDL genes were subjected to a time-kill assay to evaluate the synergistic effects. An in silico docking analysis was conducted to simulate the interactions between BLI-489 and the different families of CHDLs. The in vivo activities of this combination were assessed using a Caenorhabditis elegans survival assay and a mouse pneumonia model.

Results: Chequerboard analysis showed that imipenem and BLI-489 had a synergistic effect on 14.3, 92.9, 100, 16.7 and 100% of MBL-, OXA-23-, OXA-24-like-, OXA-51-like- and OXA-58-producing CRAb isolates, respectively. In the time-kill assay, imipenem and BLI-489 showed synergy against OXA-24-like-, OXA-51-like- and OXA-58-, but not OXA-23-producing CRAb isolates after 24 h. The in silico docking analysis showed that BLI-489 could bind to the active sites of OXA-24 and OXA-58 to confer strong inhibition activity. The combination of imipenem and BLI-489 exhibited synergistic effects for the rescue of CRAb-infected C. elegans and mice.

Conclusions: Imipenem combined with BLI-489 has synergistic effects against CHDL-producing CRAb isolates.

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