ATLS2021-PA (A Sphingolipid mimetic): Upcoming Host Directed Therapy for Acute and MDR Tuberculosis

Abstract

Several reports have shown that reduced Sphingolipids content in the lungs largely contributes to the outcome of Tuberculosis diseases. In this context, our pioneer study has advocated that Sphingosine -1 phosphate (a central Sphingolipid metabolite) can help host in limiting Mycobacterium tuberculosis burden in lungs by their virtue of tweaking M1 retuning of infected macrophages. This indicated that S1P may serve as anti-tubercular regimen, however allergic and autoimmune manifestation of S-1P refrain its further use as anti-tubercular Drugs. In view of this limitation, and high demand of developing newer host directed anti tubercular regimen, we explored whether enhancing / boosting Sphingolipids levels via de novo pathways by our patented drugs ATLS2021 and PA would also help host in controlling mycobacterial infection. Our results prudently demonstrated that ATLS2021 was effective in controlling survival of both wild type and MDR strain of TB in various models we tested. Our results further demonstrated the influence of ATLS2021 on NO mediated killing of mycobacteria which indicated one of most possible anti-mycobacterial mechanism of ATLS2021. Additionally, ATLS2021 lowered the IC50 value of Rifampicin for both wild-type and MDR TB by sensitizing the MDR clinical isolate of Mycobacterium tuberculosis to Rifampicin-mediated killing. ATLS2021 induced immunogenic responses in blood derived CD14+ macrophages from both healthy donors as well as MDR-TB patient demonstrating immune adjuvant potential of ATLS2021. Real time PCR data demonstrated that ATLS2021 enhanced the expression of almost all key enzymes involved in the Sphingolipid biosynthesis pathways in the CD14 positive monocytes from healthy donors and MDR TB patients. Taken together these results potentially advocated that ATLS2021 based approach is potentially immunogenic interventions against TB.