Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin.
Fabiana BisaroClay D Jackson-LittekenJenna C McGuffeyAnna J HooppawSophie BodrogLeila JebeliJuan C Ortiz-MarquezTim van OpijnenNichollas E ScottGisela Di VenanzioMario F FeldmanPublished in: bioRxiv : the preprint server for biology (2024)
Acinetobacter baumannii causes life-threatening infections that are becoming difficult to treat due to increasing rates of multi-drug resistance (MDR) among clinical isolates. This has led the World Health Organization and the CDC to categorize MDR A. baumannii as a top priority for the research and development of new antibiotics. Colistin is the last-resort antibiotic to treat carbapenem-resistant A. baumannii . Not surprisingly, reintroduction of colistin has resulted in the emergence of colistin-resistant strains. Diclofenac is a nonsteroidal anti-inflammatory drug used to treat pain and inflammation associated with arthritis. In this work, we show that diclofenac sensitizes colistin-resistant A. baumannii clinical strains to colistin, in vitro and in a murine model of pneumonia. Diclofenac also reduced the colistin MIC of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates. Transcriptomic and proteomic analyses revealed an upregulation of oxidative stress-related genes and downregulation of type IV pili induced by the combination treatment. Notably, the concentrations of colistin and diclofenac effective in the murine model were substantially lower than those determined in vitro , implying a stronger synergistic effect in vivo compared to in vitro . A pilA mutant strain, lacking the primary component of the type IV pili, became sensitive to colistin in the absence of diclofenac. This suggest that the downregulation of type IV pili is key for the synergistic activity of these drugs in vivo and indicates that colistin and diclofenac exert an anti-virulence effect. Together, these results suggest that the diclofenac can be repurposed with colistin to treat MDR A. baumannii .
Keyphrases
- acinetobacter baumannii
- multidrug resistant
- drug resistant
- pseudomonas aeruginosa
- klebsiella pneumoniae
- gram negative
- escherichia coli
- oxidative stress
- cystic fibrosis
- biofilm formation
- cell proliferation
- anti inflammatory
- drug delivery
- induced apoptosis
- staphylococcus aureus
- intensive care unit
- long non coding rna
- chronic pain
- cancer therapy
- poor prognosis
- single cell
- antimicrobial resistance
- ischemia reperfusion injury
- electronic health record
- endoplasmic reticulum stress
- mechanical ventilation