Enhanced Fe 3+ binding through cooperativity of 3-hydroxypyridin-4-one groups within a linear co-polymer: wrapping effec
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Enhanced Fe3+ binding through cooperativity of 3hydroxypyridin-4-one groups within a linear co-polymer: wrapping effect leading to superior antimicrobial activity Roger Gumbau-Brisa . M. Trisha C. Ang . Bruce E. Holbein . Matthias Bierenstiel
Received: 11 March 2020 / Accepted: 23 September 2020 Ó Springer Nature B.V. 2020
Abstract To tackle the rise of antibiotic resistant pathogenic microbes, iron withdrawal agents have shown considerable promise as antibiotic alternatives due to the microbes’ irreplaceable metabolic need for the essential element iron. DIBI is a water-soluble, linear co-polymer functionalized with 3-hydroxypyridin-4-one (HPO) chelators that selectively and strongly bind iron(III) in biological environments. Compared to HPO congeners, DIBI has over 1000 times higher antimicrobial activity against a broadspectrum of Gram-(?) and Gram-(-) bacteria including highly antibiotic resistant clinical isolates. Herein, we explain the enhanced antimicrobial activity of DIBI by a cooperativity effect of the linear co-polymer wrapping around three iron(III) centres. DIBI’s structural and iron(III) binding properties were investigated by comparative experiments against HPO monomer and deferiprone using chemical and physical characterization methods with direct biological implications Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10534-020-00253-1) contains supplementary material, which is available to authorized users. R. Gumbau-Brisa M. T. C. Ang M. Bierenstiel (&) Department of Chemistry, Cape Breton University, 1250 Grand Lake Road, Sydney, NS B1P 6L2, Canada e-mail: [email protected] R. Gumbau-Brisa M. T. C. Ang B. E. Holbein Chelation Partners Inc, 44 Shadybrook Crescent, Guelph, ON N1G 3G5, Canada
such as pH stability, reductive off-loading of bound iron(III), trans-membrane permeability, and competition experiments with vertebrate transferrin class iron carrier. The three iron(III) ions bound to DIBI are preferentially incorporated into a tris-bidentate chelates, which forces the linear backbone of the polymer to wrap around the complexes, as the bound iron was much less susceptible to dithionite reduction than the tris iron(III) complexes of HPO monomers and deferiprone. The results suggest a high degree of cooperativity of the polymer-bound HPO groups to effect a wrapping of the polymer backbone around the chelated iron, shielding the iron(III) centres from ready access by microbes. The structural effect of DIBI is compared to polymers containing 3-hydroxypyridin-4-one chelators that do not undergo this wrapping effect. Keywords Functional polymer Iron chelator Antibiotic properties Polymer analysis Wrapping effect Iron coordination Cooperativity 3-hydroxypyridin-4-one chelators
Introduction Antibiotic resistance of pathogenic microorganisms is a growing global problem with effective antibiotic choices dwindling (Barrasa-Villar et al. 2017), health
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