Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line

Zara Sheikh; Peta Bradbury; Tristan A Reekie; Michele Pozzoli; Paul D Robinson; Michael Kassiou; Paul M Young; Hui Xin Ong; Daniela Traini

doi:10.1016/j.ejphar.2021.174098

Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line

Eur J Pharmacol. 2021 Jul 5:902:174098. doi: 10.1016/j.ejphar.2021.174098. Epub 2021 Apr 20.

Authors

Zara Sheikh¹, Peta Bradbury², Tristan A Reekie³, Michele Pozzoli⁴, Paul D Robinson⁵, Michael Kassiou⁶, Paul M Young¹, Hui Xin Ong⁷, Daniela Traini⁸

Affiliations

¹ Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
² Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia; Discipline of Medicine, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
³ Research School of Chemistry, Australian National University, Canberra, Australia.
⁴ Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia.
⁵ Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia.
⁶ School of Chemistry, The University of Sydney, Sydney, Australia.
⁷ Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Electronic address: ong.hui@sydney.edu.au.
⁸ Respiratory Technology, The Woolcock Institute of Medical Research, Glebe, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Electronic address: daniela.traini@sydney.edu.au.

PMID: 33848541
DOI: 10.1016/j.ejphar.2021.174098

Abstract

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and ¹H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by ¹H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by ¹H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.

Keywords: Colistin; CuFi-1; Cystic fibrosis; Ibuprofen; Inflammation; Tobramycin.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Anti-Bacterial Agents / toxicity
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / toxicity
Cell Line
Cell Survival / drug effects
Colistin / analogs & derivatives
Colistin / chemistry
Colistin / pharmacology*
Colistin / toxicity
Cystic Fibrosis / drug therapy*
Drug Combinations
Humans
Ibuprofen / chemistry
Ibuprofen / pharmacology
Ibuprofen / toxicity
Inflammation / chemically induced
Inflammation / drug therapy
Interleukin-8 / metabolism
Lipopolysaccharides / toxicity
Pseudomonas aeruginosa / drug effects
Tobramycin / chemistry
Tobramycin / pharmacology*
Tobramycin / toxicity

Substances

Anti-Bacterial Agents
Anti-Inflammatory Agents, Non-Steroidal
CXCL8 protein, human
Drug Combinations
Interleukin-8
Lipopolysaccharides
colistinmethanesulfonic acid
Tobramycin
Ibuprofen
Colistin