Transcriptomic interplay between Acinetobacter baumannii , human macrophage and polymyxin.

Area of Science:

• Microbiology and Immunology
• Host-Pathogen Interactions
• Antimicrobial Resistance

Background:

• Optimizing antibiotic therapy requires understanding host-pathogen-drug interactions.
• Bacterial resistance to antibiotics, particularly against challenging pathogens like Acinetobacter baumannii, necessitates novel therapeutic strategies.
• The role of host immune cells, such as macrophages, in modulating bacterial response to antibiotics remains largely unexplored.

Approach:

• Dual RNA-sequencing was employed to analyze transcriptomic changes in Acinetobacter baumannii and human macrophages during co-culture infection.
• An in vitro tripartite model was utilized to investigate the complex interplay within the Acinetobacter baumannii-macrophage-polymyxin B axis.
• Specific bacterial genes (rcnB, ompW, traR/dksA) involved in stress tolerance were targeted to assess their impact on polymyxin B efficacy.

Key Points:

• Polymyxin B treatment induced significant transcriptomic alterations in Acinetobacter baumannii, including oxidative stress, disrupted metal homeostasis, and altered osmoadaptation.
• Macrophages responded to Acinetobacter baumannii infection by adapting heme catabolism, coagulation cascade, and hypoxia-inducible signaling.
• Synergistic action between macrophages and polymyxin B was observed, disrupting multiple bacterial stress tolerance mechanisms.

Conclusions:

• Targeting bacterial nickel/cobalt homeostasis (rcnB), osmotic stress defense (ompW), and stringent response (traR/dksA) enhances polymyxin B's antibacterial activity.
• Genetic disruption of these bacterial pathways significantly impairs Acinetobacter baumannii's ability to tolerate polymyxin B.
• These findings highlight potential therapeutic targets for developing novel treatments against Acinetobacter baumannii infections.