Enhanced Fe 3+ binding through cooperativity of 3-hydroxypyridin-4-one groups within a linear co-polymer: wrapping effect leading to superior antimicrobial activity
Biometals
2020 Oct 19. doi: 10.1007/s10534-020-00253-1. Online ahead of print.
Roger Gumbau-Brisa 1 2, M Trisha C Ang 1 2, Bruce E Holbein 2, Matthias Bierenstiel 3
PMID: 33074473 DOI: 10.1007/s10534-020-00253-1
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-hydroxy-pyridin-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 broad-
spectrum 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 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-hydroxy-pyridin-4-one
chelators that do not undergo this wrapping effect.

Keywords: 3-hydroxy-pyridin-4-one chelators; Antibiotic properties; Cooperativity; Functional polymer; Iron chelator; Iron coordination; Polymer analysis; Wrapping effect.


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