Short communication
Antimicrobial activity of an iron triple helicate

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Abstract

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe2L3]4+ and [Cu2(L’)2]2+ as antibacterial agents. Both molecules have been shown to bind DNA; [Fe2L3]4+ binds in the major groove and causes DNA coiling, whilst [Cu2(L’)2]2+ can act as an artificial nuclease. The work described here shows that only [Fe2L3]4+ is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe2L3]4+ binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly.

Introduction

Since their discovery in the 20th century, antibiotics have played an important role in health care. However, their widespread use has also resulted in the emergence of resistant bacteria, creating a major global problem. It is thus important that novel types of antimicrobials continue to be developed.

One target that is of interest for the development of novel antibiotics is DNA. Most of the known compounds that target DNA interact through covalent binding, intercalation or non-covalent binding in the minor groove [1], [2], [3], resulting in the inhibition of various processes such as DNA synthesis and repair. DNA-binding compounds are particularly known for their anti-tumour activity, but several of these also have antibacterial activity [1]. Molecules can be designed that bind in specific manners to DNA and an example of this is an iron triple helicate (denoted as [Fe2L3]4+; Fig. 1A) [4]. [Fe2L3]4+ is synthesised as a mixture of two enantiomers (M and P, denoting left-handed or minus, and right-handed or plus helical twists), which have different structural effects on DNA [5]. The M enantiomer binds the major groove and strongly induces coiling of DNA; the P enantiomer binding site(s) is more ambiguous and interaction of the P enantiomer with DNA results in less pronounced coiling effects.

Some metal helicates related to [Fe2L3]4+ also have DNA-binding properties. For example, the copper helicate [Cu2(L’)2]2+ binds DNA fairly strongly but, in contrast to [Fe2L3]4+, does not cause coiling of DNA. [Fe2L3]4+ and [Cu2(L’)2]2+ are made with similar imine-based ligands (Fig. 1B and C), but they differ in the number of ligands forming the supramolecular structure. Interestingly, [Cu2(L’)2]2+ can act as an artificial nuclease as it has DNA cleavage activity in the presence of peroxide [6]. The main aim of this work was to establish whether these compounds have antimicrobial activity and whether their potential target (DNA) is reached.

Section snippets

Strains and growth media

Bacillus subtilis 168 has been described previously [7]. Escherichia coli GM2163 was obtained from New England Biolabs (Hitchin, UK). Bacteria were grown in Luria broth (LB) [8] or Richards–Bolhuis (RB) medium [20 g/L glucose (Merck KGaA, Darmstadt, Germany), 10 mM ammonium sulphate (Fisher Scientific), 20 μM magnesium chloride (Merck), 7 μM calcium chloride (Merck), 0.5 μM manganese(II) chloride (Sigma–Aldrich, Gillingham, UK), 0.02 μM thiamine (Sigma–Aldrich), 0.01 μM zinc(II) chloride (Merck), 0.05 

Results and discussion

The antimicrobial activity of [Fe2L3]4+ and [Cu2(L’)2]2+ was initially tested through basic plate and liquid broth assays against the Gram-positive bacterium B. subtilis and the Gram-negative bacterium E. coli. Despite the apparent similarities of the two compounds, the preliminary experiments showed that they differed greatly in their antimicrobial activity. Whilst activity of [Fe2L3]4+ was observed, bacterial cells were not affected by [Cu2(L’)2]2+ at concentrations up to 128 mg/L (not shown).

References (13)

  • P.G. Baraldi et al.

    DNA minor groove binders as potential antitumor and antimicrobial agents

    Med Res Rev

    (2004)
  • U. Pindur et al.

    Advances in DNA-ligands with groove binding, intercalating and/or alkylating activity: chemistry, DNA-binding and biology

    Curr Med Chem

    (2005)
  • A.D. Richards et al.

    Synthetic metallomolecules as agents for the control of DNA structure

    Chem Soc Rev

    (2007)
  • M.J. Hannon et al.

    Intramolecular DNA coiling mediated by a metallo-supramolecular cylinder

    Angew Chem Int Ed Engl

    (2001)
  • I. Meistermann et al.

    Intramolecular DNA coiling mediated by metallo-supramolecular cylinders: differential binding of P and M enantiomers

    Proc Natl Acad Sci

    (2002)
  • L.J. Childs et al.

    A DNA-binding copper(I) metallosupramolecular cylinder that acts as an artificial nuclease

    Chemistry

    (2006)
There are more references available in the full text version of this article.

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