Harmine derivative ZLWH-38 ameliorates the therapeutic efficacy of colistin against XDR-Ab pneumonia by suppressing inflammatory responses.

BACKGROUND

Acinetobacter baumannii (Ab), especially extensively drug-resistant Ab strains (XDR-Ab), poses a significant threat to clinical medicine due to its high mortality rate and limited treatment options. Harmine derivatives exhibit potent anti-inflammatory and immunomodulatory effects. In this study, we aimed to investigate whether the harmine derivative ZLWH-38 combined with colistin could enhance therapeutic efficacy against XDR-Ab pneumonia by suppressing inflammatory responses.

METHODS

A lethal mouse pneumonia model of XDR-Ab was applied to evaluate the effects of ZLWH-38. Survival rates, bacterial colonization in lungs and blood, lung histopathological changes, inflammatory cytokine levels, and oxidative stress markers were assessed. Additionally, RAW264.7 cells were conducted to evaluate the anti-inflammatory effects of ZLWH-38 in vitro.

RESULTS

ZLWH-38 combined with colistin significantly improved survival rates (94%) compared to colistin (40%) or ZLWH-38 alone (40%). The combination therapy markedly reduced bacterial colonization in the lungs and blood, alleviated lung injury, and significantly suppressed the production of pro-inflammatory cytokine TNF-α, IL-6, and IL-1β in serum and lung tissue, reduced expression of genes associated with oxidative stress and pyroptosis in mouse lung tissue. ZLWH-38 demonstrated anti-inflammatory activity by inhibiting NO release, pro-inflammatory cytokine secretion, Reactive oxygen species (ROS) production, and NLR family pyrin domain containing 3 (NLRP3)-induced pyroptosis in Ab-infected RAW264.7 cells.

CONCLUSIONS

ZLWH-38 significantly enhances the therapeutic efficacy of colistin against Ab pneumonia. This study provides a promising therapeutic strategy for treating XDR-Ab pneumonia and highlights the potential of harmine derivatives in anti-infective therapy.