DIBI, a 3-hydroxypyridin-4-one chelator iron-binding polymer with enhanced antimicrobial activity

Abstract

Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria <i>S. aureus</i> and <i>A. baumannii</i>, and the fungus <i>C. albicans</i>. Compared to the small molecule iron chelators, deferiprone and deferoxamine, DIBI outclassed these by factors of 100 to 1000 for inhibition of initial growth. DIBI and a series of related co-polymers (<i>M</i>_w of 2-9 kDa) were synthesized <i>via</i> reversible addition-fragmentation chain transfer (RAFT) polymerization of a chelating 3-hydroxypyridin-4-one (HPO) methacrylamide monomer and <i>N</i>-vinylpyrrolidone (NVP). Full incorporation of the HPO monomer into the co-polymers from the reaction solution was determined by ¹H NMR spectroscopy and ranged from 4.6 to 25.6 mol%. UV-vis spectroscopy showed that all the HPO in DIBI binds readily to iron(iii) in a tris chelate mode to the maximum theoretical iron(iii) binding capacity of the co-polymer. Chemical characterization including single crystal X-ray diffraction analyses of the <i>O</i>-benzyl protected and the functional HPO monomer are discussed. By design, DIBI is highly water soluble; the highest mass fraction in water tested was 70% w/w, without the need of organic co-solvents.