Disulfiram Attenuates <i>Acinetobacter baumannii</i> -Induced Hyperinflammation by Regulating Inflammatory Pathways: Insights from RNA Sequencing

The emergence of carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) poses a major obstacle in treating sepsis, highlighting the urgent need for new therapeutic approaches. Recent studies have reported that disulfiram (DSF) exhibits antibacterial activity and potentiates meropenem activity against resistant <i>A. baumannii</i> (<i>A. baumannii</i>) isolates. The mechanisms by which DSF modulates inflammation during <i>A. baumannii</i> infection remain unclear, although DSF possesses anti-inflammatory properties by regulating the pyroptosis pathway. The present study aimed to investigate the potential effect of DSF in modulating inflammatory responses during CRAB infection. We observed DSF treatment in <i>A. baumannii</i>-infected cells resulted in inhibiting NF-κB activity and NLRP3 inflammasome formation, which decreases expression and secretion of IL-1β, IL-6, and TNF-α in human THP-1 cell-derived macrophages. Further, RNA sequencing was performed to determine how DSF suppresses the CRAB-associated inflammation. The transcriptomic data analysis revealed downregulation of genes involved in inflammatory pathways, including the NF-κB signaling pathway, toll-like receptor signaling pathway, and cytokine-cytokine receptor interaction pathway, in DSF-treated cells, which indicates its anti-inflammatory effects in suppressing <i>A. baumannii</i>-induced inflammation. Collectively, our findings demonstrate that DSF is a promising candidate for modulating inflammatory responses during CRAB infection; however, further validation through in vivo and clinical studies is necessary.