Selectivity in anti-infective minor groove binders

Research output: Contribution to conferencePaper

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.
Original languageEnglish
Number of pages18
DOIs
Publication statusPublished - 1 Nov 2017
Event3rd International Electronic Conference on Medicinal Chemistry -
Duration: 1 Nov 201730 Nov 2017
https://sciforum.net/conference/ecmc-3

Conference

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

Fingerprint

Binders
Cells
Cell membranes
Fungi
Esters
Phosphates
Amidines
DNA
Nonionic surfactants
Alkenes
Amides
Toxicity
Bacteria
Experiments

Keywords

  • minor groove binders
  • DNA
  • infectious organisms

Cite this

Suckling, C. J., & Scott, F. J. (2017). Selectivity in anti-infective minor groove binders. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, . https://doi.org/10.3390/ecmc-3-04648
Suckling, Colin J. ; Scott, Fraser J. / Selectivity in anti-infective minor groove binders. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, .18 p.
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Suckling, CJ & Scott, FJ 2017, 'Selectivity in anti-infective minor groove binders', Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, 1/11/17 - 30/11/17. https://doi.org/10.3390/ecmc-3-04648

Selectivity in anti-infective minor groove binders. / Suckling, Colin J.; Scott, Fraser J.

2017. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, .

Research output: Contribution to conferencePaper

TY - CONF

T1 - Selectivity in anti-infective minor groove binders

AU - Suckling, Colin J.

AU - Scott, Fraser J.

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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KW - infectious organisms

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M3 - Paper

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Suckling CJ, Scott FJ. Selectivity in anti-infective minor groove binders. 2017. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, . https://doi.org/10.3390/ecmc-3-04648