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

Kieswetter, Nathan S. and Ozturk, Mumin and Hlaka, Lerato and Chia, Julius Ebua and Nichol, Ryan J. O. and Cross, Jasmine M. and McGee, Leah and Tyson-Hirst, Izaak and Beveridge, Rebecca and Brombacher, Frank and Carter, Katharine C. and Suckling, Colin J. and Scott, Fraser J. and Guler, Reto (2022) Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to mycobacterium tuberculosis infection. Journal of Antimicrobial Chemotherapy, 77 (4). pp. 1061-1071. ISSN 0305-7453 (https://doi.org/10.1093/jac/dkac001)

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Abstract

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 with 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. Conclusions Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.

ORCID iDs

Kieswetter, Nathan S., Ozturk, Mumin, Hlaka, Lerato, Chia, Julius Ebua, Nichol, Ryan J. O., Cross, Jasmine M., McGee, Leah, Tyson-Hirst, Izaak, Beveridge, Rebecca ORCID logoORCID: https://orcid.org/0000-0003-0320-6496, Brombacher, Frank, Carter, Katharine C., Suckling, Colin J., Scott, Fraser J. ORCID logoORCID: https://orcid.org/0000-0003-0229-3698 and Guler, Reto;