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.

为了应对抗生素耐药性病原微生物的兴起，由于微生物对必需元素铁的代谢需求不可替代，铁戒断剂已显示出作为抗生素替代品的巨大前景。DIBI 是一种水溶性线性共聚物，用 3-羟基-吡啶-4-酮 (HPO) 螯合剂功能化，可在生物环境中选择性地和强烈地结合铁 (III)。与 HPO 同源物相比，DIBI 对广谱革兰氏 (+) 和革兰氏 (-) 细菌（包括高度耐抗生素的临床分离株）的抗菌活性高出 1000 倍以上。在这里，我们通过包裹在三个铁 (III) 中心周围的线性共聚物的协同效应来解释 DIBI 增强的抗菌活性。DIBI 的结构和铁 (III) 结合特性通过对 HPO 单体和去铁酮的比较实验研究，使用具有直接生物学意义的化学和物理表征方法，例如 pH 稳定性、结合铁 (III) 的还原卸载、跨膜渗透性、和脊椎动物转铁蛋白类铁载体的竞争实验。与 DIBI 结合的三个铁 (III) 离子优先结合到三齿螯合物，它迫使聚合物的线性骨架包裹在配合物周围，因为与HPO 单体和去铁酮的三铁 (III) 配合物相比，结合的铁对连二亚硫酸盐还原的敏感性要低得多。结果表明，与聚合物结合的 HPO 基团具有高度的协同性，以实现聚合物骨架围绕螯合铁的包裹，从而保护铁 (III) 中心不被微生物轻易接近。将 DIBI 的结构效应与不含这种包裹效应的含有 3-羟基-吡啶-4-酮螯合剂的聚合物进行比较。