Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to mycobacterium tuberculosis infection

Nathan S. Kieswetter, Mumin Ozturk, Lerato Hlaka, Julius Ebua Chia, Ryan J. O. Nichol, Jasmine M. Cross, Leah M. C. McGee, Izaak Tyson-Hirst, Rebecca Beveridge, Frank Brombacher, Katharine C. Carter, Colin J. Suckling, Fraser J. Scott, Reto Guler

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Abstract

Background: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364.Methods: The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. Results: S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared to DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low γ-H2Ax expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a ~1-log cfu reduction in mycobacterial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. Conclusion: Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.
Original languageEnglish
Pages (from-to)1061-1071
Number of pages11
JournalJournal of Antimicrobial Chemotherapy
Volume77
Issue number4
Early online date25 Jan 2022
DOIs
Publication statusPublished - 25 Jan 2022

Keywords

  • intracellular mycobactericidal activity
  • macrophages
  • non-ionic surfactant vesicles

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