Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to <i>Mycobacterium tuberculosis</i> infection

Kieswetter, Nathan Scott; 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

doi:10.1093/jac/dkac001

Cited by 6 publications

(11 citation statements)

References 22 publications

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“…The DNA oligomer itself, 5′-CGCATATATGCG-3′, was shown by nMS to have both single-stranded DNA [SS] in charge states 4- and 3-, and double-stranded DNA [DS] in charge states 5- and 4- ( Figure 4 ), which is typical of these experiments [ 11 ]. The nMS of DNA sequence 5′-CGCATATATGCG-3′ in the presence of S-MGB-219 showed that it bound to double-stranded DNA as a dimer [DS+2M] in charge states 5- and 4- ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 89%

“…The test oligonucleotide, d(5′-CGCATATATGCG-3′), is designed to identify binders to AT-rich regions; however, to expand the scope of the thermal binding assay, S-MGB-3 and S-MGB-219 were also investigated using genomic DNA from salmon, using S-MGB-3 as a comparator ( Figure 3 ). Salmon is commonly used as an easily accessible, cheap source of genomic DNA, and has been used in early-stage target-binding studies of S-MGBs previously [ 11 ]. S-MGB-219 had a substantial T m increase of 8.0 °C, compared to 12.6 °C for S-MGB-3 , the latter of which is in line with previous work on S-MGB-3 (manuscript in preparation).…”

Section: Resultsmentioning

confidence: 99%

“…Strathclyde minor groove binders (S-MGBs), based loosely upon the structure of the natural product distamycin ( 3 ), have been shown to have anti-infective activity against bacteria, fungi, parasites and viruses ( Figure 2 ) [ 10 , 11 , 12 , 13 , 14 , 15 ]. The structural characteristics of the most significant S-MGBs include replacement of the N -terminal formyl group in distamycin with an aromatic ring and one of the amide links being replaced with the isosteric alkene, as represented by 4 – 6 ( Figure 3 ).…”

Section: Introductionmentioning

confidence: 99%

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Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

Perieteanu

McGee²,

Shaw³

et al. 2022

IJMS

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The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

Perieteanu

McGee²,

Shaw³

et al. 2022

IJMS

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“…S-MGBs are analogues of the natural product distamycin, which target multiple sites on bacterial DNA and are active against M. tuberculosis. , We demonstrate that decrease in intracellular mycobacteria corresponds with a greater association of mycobacterial phagosomes with lysosomal markers. Finally, the efficacy of C13 alone and in combination with the antibiotics and compounds was also demonstrated in an in vivo model of infection using larvae of the waxworm Galleria mellonella.…”

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confidence: 99%

MptpB Inhibitor Improves the Action of Antibiotics against Mycobacterium tuberculosis and Nontuberculous Mycobacterium avium Infections

Rodríguez-Fernández,

Botella,

Cavet

et al. 2023

ACS Infect. Dis.

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Treatment of Mycobacterium tuberculosis and Mycobacterium avium infections requires multiple drugs for long time periods. Mycobacterium protein-tyrosine-phosphatase B (MptpB) is a key M. tuberculosis virulence factor that subverts host antimicrobial activity to promote intracellular survival. Inhibition of MptpB reduces the infection burden in vivo and offers new opportunities to improve current treatments. Here, we demonstrate that M. avium produces an MptpB orthologue and that the MptpB inhibitor C13 reduces the M. avium infection burden in macrophages. Combining C13 with the antibiotics rifampicin or bedaquiline showed an additive effect, reducing intracellular infection of both M. tuberculosis and M. avium by 50%, compared to monotreatment with antibiotics alone. This additive effect was not observed with pretomanid. Combining C13 with the minor groove-binding compounds S-MGB-362 and S-MGB-363 also reduced the M. tuberculosis intracellular burden. Similar additive effects of C13 and antibiotics were confirmed in vivo using Galleria mellonella infections. We demonstrate that the reduced mycobacterial burden in macrophages observed with C13 treatments is due to the increased trafficking to lysosomes.

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“…Their favorable cytotoxicity profiles to mammalian cells give them selectivity indices that make them suitable for development as novel drugs. This has enabled extensive in vitro and several in vivo experiments to provide proof of concept for S-MGBs as a novel class of anti-infective agent against bacterial, fungal, viral, and parasitic infections. − One of these compounds, MGB-BP-3 (Figure ) has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease (NCT03824795). MGB-BP-3 also has potent (<1 μg/mL) antibacterial activity against methicillin-resistant and methicillin-susceptible Staphylococcus spp., Streptococcus spp., and vancomycin-resistant and vancomycin-susceptible Enterococcus spp .…”

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confidence: 99%

Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3

et al. 2022

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MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease. Its precise mechanism of action and the origin of limited activity against Gram-negative pathogens are relatively unknown. Herein, treatment with MGB-BP-3 alone significantly inhibited the bacterial growth of the Gram-positive, but not Gram-negative, bacteria as expected. Synergy assays revealed that inefficient intracellular accumulation, through both permeation and efflux, is the likely reason for lack of Gram-negative activity. MGB-BP-3 has strong interactions with its intracellular target, DNA, in both Gram-negative and Gram-positive bacteria, revealed through ultraviolet−visible (UV−vis) thermal melting and fluorescence intercalator displacement assays. MGB-BP-3 was confirmed to bind to dsDNA as a dimer using nano-electrospray ionization mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Type II bacterial topoisomerase inhibition assays revealed that MGB-BP-3 was able to interfere with the supercoiling action of gyrase and the relaxation and decatenation actions of topoisomerase IV of both Staphylococcus aureus and Escherichia coli. However, no evidence of stabilization of the cleavage complexes was observed, such as for fluoroquinolones, confirmed by a lack of induction of DSBs and the SOS response in E. coli reporter strains. These results highlight additional mechanisms of action of MGB-BP-3, including interference of the action of type II bacterial topoisomerases. While MGB-BP-3′s lack of Gram-negative activity was confirmed, and an understanding of this presented, the recognition that MGB-BP-3 can target DNA of Gram-negative organisms will enable further iterations of design to achieve a Gram-negative active S-MGB.

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

Cited by 6 publications

References 22 publications

Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

MptpB Inhibitor Improves the Action of Antibiotics against Mycobacterium tuberculosis and Nontuberculous Mycobacterium avium Infections

Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3

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