Multi-target modulation of the AKT/NF-κB signalling axis by quercetin attenuates Stenotrophomonas maltophilia-induced pneumonia.

OBJECTIVE

Multidrug-resistant Stenotrophomonas maltophilia pneumonia lacks effective therapies. Quercetin, a natural flavonoid with anti-inflammatory properties, may offer benefit, but its mechanism remains unclear.

METHODS

We characterized a clinical S. maltophilia isolate, predicted quercetin targets via network pharmacology, validated interactions through molecular docking and 100 ns dynamics simulations, and evaluated efficacy in a murine pneumonia model using histopathology, western blotting, qPCR, and immunohistochemistry.

RESULTS

The isolated H-SMA strain exhibited multidrug resistance (resistant to β-lactams, macrolides, aminoglycosides) but remained susceptible to enrofloxacin. Network pharmacology identified eight core inflammatory/apoptotic targets (TNF, IL6, IL1B, IL10, IFNG, CASP3, BCL2, AKT1). Molecular docking and 100 ns dynamics simulations confirmed stable quercetin binding to all targets, with strongest interactions with AKT1 (-8.4 kcal/mol) and CASP3 (3-5 stable hydrogen bonds). In vivo, quercetin (100 mg/kg/d) significantly ameliorated clinical symptoms, reversed body weight loss, attenuated pulmonary histopathological damage, and restored splenic architecture, achieving efficacy comparable to enrofloxacin. Mechanistically, quercetin inhibited phosphorylation of AKT, IκBα, and NF-κB p65, restored Bcl-2/Bax balance, and reduced cleaved Caspase-3 expression. At the transcriptional level, quercetin downregulated pro-inflammatory (TNF, IL1B, IL6, IFNG) and pro-apoptotic (CASP3) genes while upregulating anti-inflammatory (IL10) and anti-apoptotic (BCL2) genes. Immunohistochemistry confirmed reduced pulmonary NF-κB p65 nuclear translocation and cleaved Caspase-3 positivity.

CONCLUSIONS

Quercetin alleviates S. maltophilia pneumonia through multi-target modulation of AKT/NF-κB signalling and apoptosis pathways, supporting its potential as host-directed therapy for drug-resistant bacterial infections.