The water-compatible optically pure metallohelices made by self-assembly of simple nonpeptidic organic components around Fe(II) ions are now recognized as a distinct subclass of helicates that exhibit similar architecture to some natural cationic antimicrobial peptides. Notably, a new series of metallohelices was recently shown to exhibit biological activity, displaying high, structure-dependent activity against bacteria. It is also important that, thanks to their properties, such metallohelices can exhibit specific interactions with biomacromolecules. Here, following our prior report on the metallohelices that have high, structure-dependent activity against bacteria, we investigated the interactions of the series of iron(II) metallohelices with DNA, which is a potential pharmacological target of this class of coordination compounds. The results obtained with the aid of biophysical and molecular biology methods show that the investigated metallohelices accumulate in eukaryotic cells and that a significant fraction of the metallohelices accumulates in the cell nucleus, allowing them to interact also with nuclear DNA. Additionally, we have demonstrated that some metallohelices have a high affinity to DNA and are able to condense/aggregate DNA molecules more efficiently than conventional DNA-condensing agents, such as polyamines. Moreover, this capability of the metallohelices correlates with their efficiency to inhibit DNA-related enzymatic activities, such as those connected with DNA transcription, catalysis of DNA relaxation by DNA topoisomerase I, and cleavage by restriction enzymes.
- MeSH
- buněčné jádro chemie metabolismus MeSH
- DNA-topoisomerasy I metabolismus MeSH
- DNA antagonisté a inhibitory genetika metabolismus MeSH
- HCT116 buňky MeSH
- inhibitory topoisomerasy I chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- optické jevy MeSH
- železnaté sloučeniny chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA-topoisomerasy I MeSH
- DNA MeSH
- inhibitory topoisomerasy I MeSH
- TOP1 protein, human MeSH Prohlížeč
- železnaté sloučeniny MeSH
A range of new water-compatible optically pure metallohelices - made by self-assembly of simple non-peptidic organic components around Fe ions - exhibit similar architecture to some natural cationic antimicrobial peptides (CAMPs) and are found to have high, structure-dependent activity against bacteria, including clinically problematic Gram-negative pathogens. A key compound is shown to freely enter rapidly dividing E. coli cells without significant membrane disruption, and localise in distinct foci near the poles. Several related observations of CAMP-like mechanisms are made via biophysical measurements, whole genome sequencing of tolerance mutants and transcriptomic analysis. These include: high selectivity for binding of G-quadruplex DNA over double stranded DNA; inhibition of both DNA gyrase and topoisomerase I in vitro; curing of a plasmid that contributes to the very high virulence of the E. coli strain used; activation of various two-component sensor/regulator and acid response pathways; and subsequent attempts by the cell to lower the net negative charge of the surface. This impact of the compound on multiple structures and pathways corresponds with our inability to isolate fully resistant mutant strains, and supports the idea that CAMP-inspired chemical scaffolds are a realistic approach for antimicrobial drug discovery, without the practical barriers to development that are associated with natural CAMPS.
- Publikační typ
- časopisecké články MeSH
