Selectivity in Anti-infective Minor Groove Binders

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.