Background: Rickettsia typhi is the causative agent of epidemic murine typhus and Rocky Mountain spotted fever. The infection can affect multiple vital organs, including the heart, lungs, kidneys, and brain. Doxycycline is the recommended treatment but inflammation, mal-response, and drug resistance may arise. No natural product inhibitors have been reported against this bacterium. Aim: The objective of this study was to establish a potential connection between autoimmune disorders triggered by R. typhi, identify therapeutic targets within its core proteome, and explore novel natural product inhibitors from Streptomyces spp. that could potentially inhibit it. Methodology: Complete proteomes of four publicly available R. typhi strains were used for pan-proteomic analysis. The fni gene product (Isopentenyl pyrophosphate isomerase) was selected as the potential drug target. Molecular docking of 607 Streptomyces-derived metabolites was performed, with top hits validated using DiffDock and Vinardo scoring. Additionally, the Absorption, Distribution, Metabolism, Excretion, and Toxicity properties of the leading compounds were assessed via pkCSM, and formulation characteristics optimized using FormulationAI. Results: Out of the 803 core proteins, associations between 14 proteins were mined for autoimmune diseases (including psoriasis, rheumatoid arthritis, optic atrophy, uveitis, even-plus syndrome, Sjogren syndrome, inflammatory bowel disease, allergic rhinitis, systemic lupus erythematosus, sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, colitis etc.). 17 core proteins were predicted as druggable. ZINC01482946 demonstrated the strongest inhibitory potential, as confirmed by DiffDock scoring, convolutional neural network-based ranking, and Vinardo scoring. It demonstrated a stable configuration and exhibited a favorable pharmacokinetic profile, with bioavailability enhanced through cyclodextrin complexation. Conclusion: To the best of our knowledge, this is the first report identifying human autoimmune associations with R. typhi and natural product inhibitors targeting the pathogen. ZINC01482946 shows potential as an effective inhibitor of R. typhi, while SBE-β-CD appears to be a promising cyclodextrin for improving its solubility and bioavailability. Clinical trial number: Not applicable.