Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype

Brooke, Daniel P.; McGee, Leah M. C.; Giordani, Federica; Cross, Jasmine M.; Khalaf, Abedawn I.; Irving, Craig; Gillingwater, Kirsten; Shaw, Craig; Carter, Katharine C.; Barrett, Michael P.; Suckling, Colin J.; Scott, Fraser J.

doi:10.1039/d1md00110h

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…The N -oxide S-MGBs, interestingly, were not found to be active against Staphylococcus aureus , in contrast to their precursors, which include some of the most active S-MGBs against Gram-positive bacteria. In another study in which the structures of S-MGB-1 , S-MGB-2 and S-MGB-3 were truncated by the removal of one pyrrole from the structure, a reduction in Gram-positive activity was also observed [ 19 ]. In other studies, antifungal activity was not found for the N -oxides either (data not reported).…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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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“…MGB-BP-3 and S-MGB-245 were prepared as previously described in refs ( 4 ) and ( 11 ), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…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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Strathclyde minor groove binders (S-MGBs) with activity against Acanthamoeba castellanii

Mcgee,

Carpinteyro Sanchez,

Perieteanu

et al. 2024

Journal of Antimicrobial Chemotherapy

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Background Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms. Objectives To synthesize and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development. Methods A panel of 12 S-MGBs was synthesized and anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays. Results and discussion S-MGB-241 has an IC50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50 > 100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTm = 1 ± 0.1°C. Conclusions Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a ‘hit’ compound that is selectively active against A. castellanii, providing a starting point from which to begin optimization of DNA binding and potency.

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Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype

Abstract: This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine.

Cited by 3 publications

References 21 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

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

Strathclyde minor groove binders (S-MGBs) with activity against Acanthamoeba castellanii

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