Alginate-Amphotericin B bifunctional conjugates have improved solubility and reduced toxicity

Alginates are a family of linear anionic polysaccharides produced by brown algae and some bacteria and consist of 1 → 4 linked β - d -mannuronic acid (M), and its C5-epimer α - l -guluronic acid (G). Research has shown that oligoguluronates possess biofilm disruption properties, which combined with their high water-solubility and low toxicity, represent ideal candidates for creating novel bifunctional antifungal compounds. The progressive increase in antifungal resistance is a major global human health threat. This intrinsic resistance illustrates the need to develop improved antifungal drugs with greater efficacy against antifungal growth, while also reducing the potential for drug toxicity, resistance and tolerance. Amphotericin B is a polyene macrolide antifungal with broad specificity but has poor water solubility and is limited by infusion-related reactions and nephrotoxicity. In this work, we developed two types of Alginate-Amphotericin B conjugates with low molecular weight oligoguluronates conjugated through the reducing end. Conjugation to amphotericin B was through the carboxylic acid group or the amine group. The Alginate-Amphotericin B conjugates have reduced toxicity towards liver cells (HepG2) and kidney cells (LLC-PK1) and highly improved solubility characteristics, while maintaining anti-fungal activity. • Alginate-AmpB conjugates have reduced toxicity towards liver cells (HepG2). • Alginate-AmpB conjugates display reduced toxicity towards kidney cells (LLC-PK1). • The water-solubility of AmpB increases over 32,000-fold when conjugated to alginate. • Alginate-AmpB conjugates have antifungal activity towards Candida albicans .