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- Title
On the Antibacterial Activity of Azacarboxylate Ligands: Lowered Metal Ion Affinities for Bis-amide Derivatives of EDTA do not mean Reduced Activity.
- Authors
Mulla, Raminder S.; Beecroft, Marikka S.; Pal, Robert; Aguilar, Juan A.; Pitarch-Jarque, Javier; García-España, Enrique; Lurie-Luke, Elena; Sharples, Gary J.; Gareth Williams, J. A.
- 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.
- Subjects
CARBOXYLATE derivatives; ANTIBACTERIAL agents; LIGANDS (Chemistry); METAL ions; BACTERIAL growth; AMIDE derivatives; ETHYLENEDIAMINETETRAACETIC acid; SUBSTITUENTS (Chemistry)
- Publication
Chemistry - A European Journal, 2018, Vol 24, Issue 28, p7137
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201800026