Volume 24, Issue 28 p. 7137-7148
Full Paper

On the Antibacterial Activity of Azacarboxylate Ligands: Lowered Metal Ion Affinities for Bis-amide Derivatives of EDTA do not mean Reduced Activity

Dr. Raminder S. Mulla

Corresponding Author

Dr. Raminder S. Mulla

Department of Chemistry, Durham University, Durham, DH1 3LE UK

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Marikka S. Beecroft

Marikka S. Beecroft

Department of Biosciences, Durham University, Durham, DH1 3LE UK

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Dr. Robert Pal

Dr. Robert Pal

Department of Chemistry, Durham University, Durham, DH1 3LE UK

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Dr. Juan A. Aguilar

Dr. Juan A. Aguilar

Department of Chemistry, Durham University, Durham, DH1 3LE UK

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Dr. Javier Pitarch-Jarque

Dr. Javier Pitarch-Jarque

Instituto de Ciencia Molecular, Universidad de Valencia, C/ Catedrático José Beltrán 2, 46980 Paterna, Valencia, Spain

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Prof. Enrique García-España

Prof. Enrique García-España

Instituto de Ciencia Molecular, Universidad de Valencia, C/ Catedrático José Beltrán 2, 46980 Paterna, Valencia, Spain

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Dr. Elena Lurie-Luke

Dr. Elena Lurie-Luke

Procter and Gamble Technical Centres Limited, Rusham Park, Whitehall Lane, Egham, Surrey, TW20 9NW UK

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Dr. Gary J. Sharples

Corresponding Author

Dr. Gary J. Sharples

Department of Biosciences, Durham University, Durham, DH1 3LE UK

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Prof. J. A. Gareth Williams

Corresponding Author

Prof. J. A. Gareth Williams

Department of Chemistry, Durham University, Durham, DH1 3LE UK

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First published: 23 March 2018
Citations: 3

Graphical Abstract

Bacteriostatic effects of ligands: The bacterial growth inhibition of azacarboxylate ligands like EDTA is generally assumed to scale with the avidity with which the ligand binds bio-relevant metal ions. Studies on the inhibition of E. coli growth by EDTA derivatives, such as the glycine-based bis-amide (AmGly2), reveal an unexpected biphasic response that suggests no simple relationship of the minimal inhibitory concentration with metal association constants.

Abstract

EDTA is widely used as an inhibitor of bacterial growth, affecting the uptake and control of metal ions by microorganisms. We describe the synthesis and characterisation of two symmetrical bis-amide derivatives of EDTA, featuring glycyl or pyridyl substituents: AmGly2 and AmPy2. Metal ion affinities (logK) have been evaluated for a range of metals (Mg2+, Ca2+, Fe3+, Mn2+, Zn2+), revealing less avid binding compared to EDTA. The solid-state structures of AmGly2 and of its Mg2+ complex have been determined crystallographically. The latter shows an unusual 7-coordinate, capped octahedral Mg2+ centre. The antibacterial activities of the two ligands and of EDTA have been evaluated against a range of health-relevant bacterial species, three Gram negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) and a Gram positive (Staphylococcus aureus). The AmPy2 ligand is the only one that displays a significant inhibitory effect against K. pneumoniae, but is less effective against the other organisms. AmGly2 exhibits a more powerful inhibitory effect against E. coli at lower concentrations than EDTA (<3 mm) or AmPy2, but loses its efficacy at higher concentrations. The growth inhibition of EDTA and AmGly2 on mutant E. coli strains with defects in outer-membrane lipopolysaccharide (LPS) structures has been assessed to provide insight into the unexpected behaviour. Taken together, the results contradict the assumption of a simple link between metal ion affinity and antimicrobial efficacy.

Conflict of interest

The authors declare no conflict of interest.