Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B Original paper

What was studied?

This experimental study investigated the antifungal efficacy of lactoferrin (LF) against a wide range of clinically relevant yeasts and molds, and its potential to act synergistically with common antifungal drugs. The authors evaluated the minimum inhibitory concentrations (MICs) of lactoferrin from three different sources and analyzed how iron saturation, digestion state, and source purity influenced LF activity and synergy with antifungals, particularly amphotericin B (AMB).

Who was studied?

The study focused on 22 yeast species and 24 mold species, using both clinical isolates and reference strains. Key organisms included Candida albicans, Cryptococcus neoformans, C. glabrata, and Saccharomyces cerevisiae. In vivo efficacy was tested using a Galleria mellonella infection model inoculated with Candida and Cryptococcus species.

What were the most important findings?

Lactoferrin displayed broad antifungal activity against yeasts. The iron-depleted (apo) form was more active than the iron-rich (holo) form, affirming that iron chelation plays a major role in LF’s antifungal function. However, synergy with amphotericin B was independent of iron saturation and instead depended on peptide fragments within LF, highlighting that proteolytic digestion enhances its efficacy.

Most critically, LF synergized strongly with AMB against 19 of 22 yeast species, producing 4-fold reductions in AMB concentrations needed to inhibit growth. This combination therapy significantly reduced fungal burden and improved survival in the Galleria mellonella model, confirming in vivo relevance. Scanning electron microscopy (SEM) imaging showed that LF disrupted fungal morphology and, when combined with AMB, induced pore formation, hyphal thinning, and capsule collapse in Candida and Cryptococcus. The LF-AMB combination also impaired key virulence traits like biofilm formation and hyphal elongation in Candida, and capsule and cell size modulation in Cryptococcus, all of which are critical to pathogenesis and immune evasion.

While LF alone exerted antifungal activity via iron sequestration and membrane damage, its synergy with AMB appears to rely on facilitating AMB’s cell entry and amplifying intracellular stress. These results underscore its multifaceted role as both an iron chelator and membrane-disrupting peptide complex.

What are the implications of this study?

This study provides compelling evidence that lactoferrin, particularly when derived from digested, iron-depleted sources, could serve as a low-toxicity, broad-spectrum antifungal adjunct. Its synergy with amphotericin B could enable lower dosing, reduce side effects, and enhance treatment efficacy against drug-resistant or biofilm-associated fungal infections. For microbiome-centered therapies, LF offers dual promise: direct suppression of fungal overgrowth and support for microbial balance via targeted pathogen reduction without broad-spectrum collateral damage. Moreover, its ability to impair fungal virulence traits suggests a novel pathway to disarm pathogenic fungi without solely relying on fungicidal pressure, potentially slowing the emergence of resistance.