Deciphering synergistic killing mechanisms of capsaicin combined with colistin against colistin-resistant Acinetobacter baumannii through metabolomics analysis.

Colistin is increasingly used as last-line therapy for A. baumannii infections. This has led to the emergence of colistin-resistant strains of A. baumannii. Therefore, exploring novel approaches to fight colistin resistance in A. baumannii is urgently required. In our previous study, we reported that capsaicin combined with colistin could effectively circumvent colistin resistance in A. baumannii. Here, we employed untargeted metabolomics to explore the global metabolic perturbations of ATCC 19606-R induced by a combination of colistin (2 μg/mL) and capsaicin (32 μg/mL) compared to each of them acting alone at 1, 4, and 24 h. Data revealed that the metabolic changes of ATCC 19606-R were initially driven by capsaicin (at 1 h) and then by colistin (at 4 h). The combination treatment induced remarkable metabolic perturbations at 4 h, which were mainly caused by colistin. This metabolic impairment continued for 24 h. Results also showed that vital metabolic pathways, such as those involved in carbohydrate, nucleotide, and amino acid metabolism, underwent significant changes. On the other hand, the combination treatment had a negligible effect on lipid metabolism. Data in this study suggest that a combination of capsaicin and colistin is a promising candidate for treating A. baumannii infections.