Selectivity in Anti-infective Minor Groove Binders

Colin J. Suckling, Fraser Scott

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Minor groove binders for DNA synthesised at the University of Strathclyde (S-MGBs) have been successfully shown to be active against a wide range of infectious organisms including bacteria, fungi, and parasites in particular through collaborations with a worldwide network of partners. S-MGBs can be obtained from a wide range of structures and physicochemical properties that influence the S-MGB’s effect on a given class of target organism. A dominant feature that determines selectivity is access of the S-MGB to the DNA of the target organism which requires passing through the external cell membrane or cell wall and any further intracellular barriers. For infectious organisms that reside inside the host mammalian cell, passage through the mammalian cell membrane must also occur. Experiments have shown that S-MGBs containing alkene links in place of an amide are in general most effective against all the infective agents studied but significant activity against some fungi has also been observed in S-MGBs with amidine links. More subtle effects in anti-fungal activity have also been observed relating to the structure of the fungal cell wall: dicationic S-MGBs were active against C. neoformans, which lacks phosphate esters in its outer cell wall, but inactive against C. albicans, whose cell wall contains phosphate esters to which the dicationic S-MGB can bind thereby preventing cell penetration. Comparison of toxicity with mammalian cells shows significant but not optimal selectivity indices for the best compounds. In the case of M. tuberculososis, improved selectivity indices were obtained using non-ionic surfactant vesicles in the formulation. Together these results are helpful to identify clusters of S-MGBs that can be optimised to be selective against a given infectious agent.
LanguageEnglish
Title of host publication3rd International Electronic Conference on Medicinal Chemistry
DOIs
Publication statusPublished - 1 Nov 2017
Event3rd International Electronic Conference on Medicinal Chemistry -
Duration: 1 Nov 201730 Nov 2017
https://ecmc-3.sciforum.net/ (Link to Conference Website)

Conference

Conference3rd International Electronic Conference on Medicinal Chemistry
Period1/11/1730/11/17
OtherWebinar
Internet address

Fingerprint

Cell Wall
Esters
Fungi
Phosphates
Cell Membrane
Fungal Structures
Amidines
DNA
Alkenes
Surface-Active Agents
Amides
Parasites
Bacteria

Cite this

Suckling, C. J., & Scott, F. (2017). Selectivity in Anti-infective Minor Groove Binders. In 3rd International Electronic Conference on Medicinal Chemistry https://doi.org/10.3390/ecmc-3-04648
Suckling, Colin J. ; Scott, Fraser. / Selectivity in Anti-infective Minor Groove Binders. 3rd International Electronic Conference on Medicinal Chemistry . 2017.
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abstract = "Minor groove binders for DNA synthesised at the University of Strathclyde (S-MGBs) have been successfully shown to be active against a wide range of infectious organisms including bacteria, fungi, and parasites in particular through collaborations with a worldwide network of partners. S-MGBs can be obtained from a wide range of structures and physicochemical properties that influence the S-MGB’s effect on a given class of target organism. A dominant feature that determines selectivity is access of the S-MGB to the DNA of the target organism which requires passing through the external cell membrane or cell wall and any further intracellular barriers. For infectious organisms that reside inside the host mammalian cell, passage through the mammalian cell membrane must also occur. Experiments have shown that S-MGBs containing alkene links in place of an amide are in general most effective against all the infective agents studied but significant activity against some fungi has also been observed in S-MGBs with amidine links. More subtle effects in anti-fungal activity have also been observed relating to the structure of the fungal cell wall: dicationic S-MGBs were active against C. neoformans, which lacks phosphate esters in its outer cell wall, but inactive against C. albicans, whose cell wall contains phosphate esters to which the dicationic S-MGB can bind thereby preventing cell penetration. Comparison of toxicity with mammalian cells shows significant but not optimal selectivity indices for the best compounds. In the case of M. tuberculososis, improved selectivity indices were obtained using non-ionic surfactant vesicles in the formulation. Together these results are helpful to identify clusters of S-MGBs that can be optimised to be selective against a given infectious agent.",
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Suckling, CJ & Scott, F 2017, Selectivity in Anti-infective Minor Groove Binders. in 3rd International Electronic Conference on Medicinal Chemistry . 3rd International Electronic Conference on Medicinal Chemistry, 1/11/17. https://doi.org/10.3390/ecmc-3-04648

Selectivity in Anti-infective Minor Groove Binders. / Suckling, Colin J.; Scott, Fraser.

3rd International Electronic Conference on Medicinal Chemistry . 2017.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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T1 - Selectivity in Anti-infective Minor Groove Binders

AU - Suckling, Colin J.

AU - Scott, Fraser

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Minor groove binders for DNA synthesised at the University of Strathclyde (S-MGBs) have been successfully shown to be active against a wide range of infectious organisms including bacteria, fungi, and parasites in particular through collaborations with a worldwide network of partners. S-MGBs can be obtained from a wide range of structures and physicochemical properties that influence the S-MGB’s effect on a given class of target organism. A dominant feature that determines selectivity is access of the S-MGB to the DNA of the target organism which requires passing through the external cell membrane or cell wall and any further intracellular barriers. For infectious organisms that reside inside the host mammalian cell, passage through the mammalian cell membrane must also occur. Experiments have shown that S-MGBs containing alkene links in place of an amide are in general most effective against all the infective agents studied but significant activity against some fungi has also been observed in S-MGBs with amidine links. More subtle effects in anti-fungal activity have also been observed relating to the structure of the fungal cell wall: dicationic S-MGBs were active against C. neoformans, which lacks phosphate esters in its outer cell wall, but inactive against C. albicans, whose cell wall contains phosphate esters to which the dicationic S-MGB can bind thereby preventing cell penetration. Comparison of toxicity with mammalian cells shows significant but not optimal selectivity indices for the best compounds. In the case of M. tuberculososis, improved selectivity indices were obtained using non-ionic surfactant vesicles in the formulation. Together these results are helpful to identify clusters of S-MGBs that can be optimised to be selective against a given infectious agent.

AB - Minor groove binders for DNA synthesised at the University of Strathclyde (S-MGBs) have been successfully shown to be active against a wide range of infectious organisms including bacteria, fungi, and parasites in particular through collaborations with a worldwide network of partners. S-MGBs can be obtained from a wide range of structures and physicochemical properties that influence the S-MGB’s effect on a given class of target organism. A dominant feature that determines selectivity is access of the S-MGB to the DNA of the target organism which requires passing through the external cell membrane or cell wall and any further intracellular barriers. For infectious organisms that reside inside the host mammalian cell, passage through the mammalian cell membrane must also occur. Experiments have shown that S-MGBs containing alkene links in place of an amide are in general most effective against all the infective agents studied but significant activity against some fungi has also been observed in S-MGBs with amidine links. More subtle effects in anti-fungal activity have also been observed relating to the structure of the fungal cell wall: dicationic S-MGBs were active against C. neoformans, which lacks phosphate esters in its outer cell wall, but inactive against C. albicans, whose cell wall contains phosphate esters to which the dicationic S-MGB can bind thereby preventing cell penetration. Comparison of toxicity with mammalian cells shows significant but not optimal selectivity indices for the best compounds. In the case of M. tuberculososis, improved selectivity indices were obtained using non-ionic surfactant vesicles in the formulation. Together these results are helpful to identify clusters of S-MGBs that can be optimised to be selective against a given infectious agent.

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Suckling CJ, Scott F. Selectivity in Anti-infective Minor Groove Binders. In 3rd International Electronic Conference on Medicinal Chemistry . 2017 https://doi.org/10.3390/ecmc-3-04648