Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection.
J Antimicrob Chemother
; 77(4): 1061-1071, 2022 03 31.
Article
in En
| MEDLINE
| ID: mdl-35084027
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 DNAS-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 â¼1 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.
Full text:
1
Database:
MEDLINE
Main subject:
Tuberculosis
/
Mycobacterium tuberculosis
Limits:
Animals
Language:
En
Year:
2022
Type:
Article