@article{Kieswetter2022,
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 $\gamma$-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 mycobacter-ial 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.},
author = {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 M C 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},
doi = {10.1093/JAC/DKAC001},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kieswetter et al. - 2022 - Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response t.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,antitubercular agents,chemical surfactants,chemokines,cytokine,dimers,dna,dna topoisomerases,enzyme-linked immunosorbent assay,flow cytometry,fund{\_}ack,histology,immune response,infections,intranasal administration,lung,macrophages,mass spectrometry,mice,mycobacterium tuberculosis,neutrophils,noninvasive ventilation,original,pharmacokinetics,proof of concept studies,pulmonary surfactants,tuberculosis,type i,vaccine information sheets,vesicle},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {4},
pages = {1061--1071},
pmid = {35084027},
publisher = {Oxford University Press (OUP)},
title = {{Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to \textit{Mycobacterium tuberculosis} infection}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac001/6515318},
volume = {77},
year = {2022}
}

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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 mycobacter-ial 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.","author":[{"propositions":[],"lastnames":["Kieswetter"],"firstnames":["Nathan","S"],"suffixes":[]},{"propositions":[],"lastnames":["Ozturk"],"firstnames":["Mumin"],"suffixes":[]},{"propositions":[],"lastnames":["Hlaka"],"firstnames":["Lerato"],"suffixes":[]},{"propositions":[],"lastnames":["Chia"],"firstnames":["Julius","Ebua"],"suffixes":[]},{"propositions":[],"lastnames":["Nichol"],"firstnames":["Ryan","J","O"],"suffixes":[]},{"propositions":[],"lastnames":["Cross"],"firstnames":["Jasmine","M"],"suffixes":[]},{"propositions":[],"lastnames":["McGee"],"firstnames":["Leah","M","C"],"suffixes":[]},{"propositions":[],"lastnames":["Tyson-Hirst"],"firstnames":["Izaak"],"suffixes":[]},{"propositions":[],"lastnames":["Beveridge"],"firstnames":["Rebecca"],"suffixes":[]},{"propositions":[],"lastnames":["Brombacher"],"firstnames":["Frank"],"suffixes":[]},{"propositions":[],"lastnames":["Carter"],"firstnames":["Katharine","C"],"suffixes":[]},{"propositions":[],"lastnames":["Suckling"],"firstnames":["Colin","J"],"suffixes":[]},{"propositions":[],"lastnames":["Scott"],"firstnames":["Fraser","J"],"suffixes":[]},{"propositions":[],"lastnames":["Guler"],"firstnames":["Reto"],"suffixes":[]}],"doi":"10.1093/JAC/DKAC001","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kieswetter et al. - 2022 - Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response t.pdf:pdf","issn":"0305-7453","journal":"Journal of Antimicrobial Chemotherapy","keywords":"OA,antitubercular agents,chemical surfactants,chemokines,cytokine,dimers,dna,dna topoisomerases,enzyme-linked immunosorbent assay,flow cytometry,fund_ack,histology,immune response,infections,intranasal administration,lung,macrophages,mass spectrometry,mice,mycobacterium tuberculosis,neutrophils,noninvasive ventilation,original,pharmacokinetics,proof of concept studies,pulmonary surfactants,tuberculosis,type i,vaccine information sheets,vesicle","mendeley-tags":"OA,fund_ack,original","month":"jan","number":"4","pages":"1061–1071","pmid":"35084027","publisher":"Oxford University Press (OUP)","title":"Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to <i>Mycobacterium tuberculosis</i> infection","url":"https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac001/6515318","volume":"77","year":"2022","bibtex":"@article{Kieswetter2022,\r\nabstract = {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 $\\gamma$-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 mycobacter-ial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. 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