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

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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 ORCID logoORCID: https://orcid.org/0000-0002-9896-0450, 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;
CORE (COnnecting REpositories)