Streptomyces taklimakanensis sp. nov. TRM43335 produces 3-indole carbaldehyde a promising inhibitor of carbapenem-resistant Acinetobacter baumannii: In vitro and in vivo evaluations.

Abstract

OBJECTIVE: We aimed to identify novel inhibitors against carbapenem-resistant Acinetobacter baumannii (CR-AB) derived from Streptomyces taklimakanensis sp. nov. TRM43335 and to evaluate their dual antibiofilm and anti-inflammatory mechanisms. METHODS: The TRM43335 extract yielded 3-indole carbaldehyde through bioactivity-guided isolation. Its antibiofilm activity was assessed using crystal violet, extracellular polymeric substances (EPS) quantification, motility, confocal laser scanning microscopy (CLSM), reverse transcription quantitative polymerase chain reaction (RT-qPCR) targeting ompA (outer-membrane protein A), bfmR (biofilm-associated regulator), and bap (biofilm-associated protein), and molecular docking. In vivo efficacy was evaluated in a murine pneumonia model by measuring bacterial burden, histology, and expression of inflammation-related proteins (Toll-like receptor 4 [TLR4], nuclear factor-κB [NF-κB], NOD-like receptor family pyrin domain-containing 3 [NLRP3], and mitogen-activated protein kinase [MAPK] pathway components) via western blotting. RESULTS: 3-Indole carbaldehyde significantly reduced CR-AB biofilm, suppressed EPS/extracellular proteins, and impaired swarming motility, with marked downregulation of biofilm genes. In mice, 3-indole carbaldehyde treatment decreased lung bacterial load, improved histopathology and inhibited expression of TLR4, NF-κB, NLRP3, and MAPK pathway components (including p38, extracellular signal-regulated kinase 2 [ERK2], c-Jun N-terminal kinase [JNK], tumor necrosis factor receptor-associated factor 6 [TRAF6], and tumor necrosis factor alpha [TNF-α]), indicating suppression of inflammasome and MAPK signaling. CONCLUSION: 3-indole carbaldehyde simultaneously inhibits CR-AB biofilm formation and attenuates pulmonary inflammation. Thus, it represents a novel dual-action therapeutic strategy that addresses the key limitations of single-target antibiotics such as meropenem. Coupled with a favorable safety profile, it is a highly promising candidate for treating drug-resistant CR-AB infections.