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- Title
Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection.
- Authors
Kieswetter, Nathan S.; Ozturk, Mumin; Hlaka, Lerato; Chia, Julius Ebua; Nichol, Ryan J. O.; Cross, Jasmine M.; McGee, Leah M. C.; Tyson-Hirst, Izaak; Beveridge, Rebecca; Brombacher, Frank; Carter, Katharine C.; Suckling, Colin J.; Scott, Fraser J.; Guler, Reto
- Abstract
<bold>Background: </bold>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.<bold>Objectives: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2022, Vol 77, Issue 4, p1061
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkac001