Lactoferrin and Derived Peptides: Antifungal Mechanisms, Azole Synergy, and Links to Microbial Metallomics

What was reviewed?

This mini-review synthesizes evidence on the antifungal activity of lactoferrin and its derived peptides, detailing spectrum of activity, mechanisms, and drug synergy across yeasts and molds. It covers intact lactoferrin, lactoferricin, lactoferrampin, and Lf(1–11), and summarizes structure–function determinants relevant to fungal killing and adjuvancy.

Who was reviewed?

The paper surveys in vitro and mechanistic studies across clinically important fungi, including multiple Candida spp., Cryptococcus spp., Aspergillus fumigatus, dermatophytes such as Trichophyton spp. and Microsporum canis, plant-pathogenic molds, and model yeasts, incorporating data generated with human, bovine, porcine, and recombinant lactoferrin or peptides thereof.

Most important findings and microbiome-relevant interpretation

Lactoferrin is a multifunctional iron-binding glycoprotein with broad antifungal activity that operates through membrane disruption, immunomodulation, and metal sequestration. Evidence shows that apo-lactoferrin restricts fungal growth by chelating Fe³⁺, a cornerstone of nutritional immunity, while many candidacidal effects are iron-independent and result from direct perturbation of fungal membranes, ionic leakage, mitochondrial dysfunction, and apoptosis-like death. The review documents synergy with azoles such as fluconazole, itraconazole, clotrimazole, and ketoconazole across wild-type and resistant Candida strains, with additional interactions reported for amphotericin B and nystatin in selected species. The peptide derivatives exhibit greater potency than the intact protein. Lactoferricin B is rapidly internalized, collapses proton gradients, forms pores, and shows wide activity, including against dermatophytes; importantly for Microsporum canis, Table 1 reports a minimum inhibitory concentration of 40 μg/ml for lactoferricin B. Lactoferrampin and Lf(1–11) also permeabilize membranes and display synergistic killing with fluconazole under specific dosing sequences.

These mechanisms connect directly to microbial metallomics. Lactoferrin and its domains bind Fe³⁺ with high affinity and can also bind Cu²⁺, Zn²⁺, and Mn²⁺, situating these molecules at the interface of metal trafficking, fungal metal homeostasis, and host defense. By altering extracellular iron availability and engaging fungal membranes, lactoferrin-based interventions perturb metal-dependent respiratory and redox processes in pathogens, while derived peptides provide metal-agnostic membrane disruption that complements metallomic deprivation. This dual leverage on metal limitation and membrane damage supports their use as microbiome-targeted antifungals that both reduce pathogen fitness and lessen the likelihood of resistance emergence.

Greatest implications of the review

For microbiome-signature frameworks, lactoferrin and its peptides offer a mechanistically coherent class of interventions that align with metal-centric host–pathogen competition and immunologic containment. Clinically, they are promising adjuvants to azoles for azole-refractory candidiasis and plausible candidates for dermatophyte management, including M. canis, where peptide potency and synergy may reduce required azole exposures. The structure–activity insights summarized here further indicate that rational sequence optimization can tune charge, hydrophobicity, and helicity to maximize antifungal performance while preserving metallomic mechanisms related to iron sequestration. Translational priorities include standardized potency assays across species, peptide pharmacokinetics and safety, and in vivo confirmation of metallomic pathway engagement during therapy.

Citation

Fernandes KE, Carter DA. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Front Microbiol. 2017;8:2. https://doi.org/10.3389/fmicb.2017.00002