A remarkable rise in antibiotic resistance has necessitated the exploration of novel approaches for combating several bacterial illnesses. Now, a recent study published in the International Journal of Antimicrobial Agents, reports that iron triple helicate ([Fe₂L₃]⁴⁺), a synthetic metallomolecule, exhibits bactericidal activity by binding to the major groove of bacterial DNA, causing coiling and preventing its replication. Owing to the direct interaction with DNA, the molecule has been suggested to overcome multi-drug resistance.

Adair D Richards from the University of Warwick, Coventry, UK, and co-workers, conducted the study to evaluate the antimicrobial activity of two synthetic metallomolecules, [Fe₂L₃]⁴⁺ and tetranuclear copper(II) complex [Cu₂L'₂]²⁺ on Bacillus subtilis and Escherichia coli. While both molecules have the ability to bind to DNA, the study showed the bactericidal activity of [Fe₂L₃]⁴⁺ within a few minutes of introduction, which was demonstrated by its binding to the major groove of DNA and the resultant coiling. The [Cu₂L'₂]²⁺ was proposed to function as an artificial nuclease. The study findings demonstrated [Fe₂L₃]⁴⁺ to be an effective bactericide against E coli and B subtilis.

The iron triple helicate contains three organic strands wrapped around two iron centers to form a helix structure, which perfectly fits into the major groove of DNA helix. The high positive charge of [Fe₂L₃]⁴⁺ further enhances its ability to bind to the negatively charged DNA. Researchers suggested that the coiling caused as a result of the iron triple helicate’s binding to the DNA, prevents the latter’s interaction with other molecules, thereby hindering the associated chemical or biological processes.

Several studies have established that [Fe₂L₃]⁴⁺ (L=C₂₅H₂₀N₄), a synthetic supramolecular tetracationic iron cylinder, induces bending and intramolecular coiling of DNA in vitro by binding to the major groove of DNA. Malina et al (Nucleic Acids Research, 2008) evaluated the interaction of pure enantiomers of [Fe₂L₃]⁴⁺ with plasmid DNA (pUC19 and pSP73) and calf thymus DNA using biochemical and molecular biology methods. The study findings reported that the enantiomers, specifically the M enantiomer, preferentially bind to the regularly alternating purine-pyrimidine sequences and extensively unwind DNA.

In addition to the bactericidal property, iron triple helicate molecule has also been reported to exhibit antitumor activity. A study conducted by Hotze et al (Chemistry and Biology, 2008) to examine the apoptotic and cytostatic effect of [Fe₂L₃]⁴⁺Cl₄, showed that the molecule reduced mitochondrial activity, inhibited cell cycle, and augmented apoptotic cell death. It was also noted that unlike conventional anticancer drugs, iron triple helicate was not genotoxic.

The development of drug-resistance, primarily due to improper or overuse of antibiotics, necessitates the shift from first-line to second- or third-line antibiotics, which could be toxic. It could also lead to prolonged hospital stays, high cost of care, and increased mortality rate. Discovery of such molecular interventions could aid in designing unique therapeutic strategies to tackle the challenge of microbial drug-resistance.

References

1. Richards AD, Rodger A, Hannon MJ, Bolhuis A. Antimicrobial activity of an iron triple helicate. Int J Antimicrob Agents. 2009 May;33(5):469-72.

2. New antibiotics could come from a DNA binding compound that kills bacteria in 2 minutes. Press Release. University of Warwick. Last Accessed, 10 June, 2009.

3. Malina J, Hannon MJ, Brabec V. DNA binding of dinuclear iron(II) metallosupramolecular cylinders. DNA unwinding and sequence preference. Nucleic Acids Res. 2008 Jun;36(11):3630-8.

4. Hotze AC, Hodges NJ, Hayden RE, et al. Supramolecular Iron Cylinder with Unprecedented DNA Binding Is a Potent Cytostatic and Apoptotic Agent without Exhibiting Genotoxicity. Chem Biol. 2008 Dec 22;15(12):1258-67.