Abstract
Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. LF was broadly and consistently active against all yeast species tested (MICs, 8 to 64 μg/ml), with the extent of activity being strongly affected by iron saturation. LF was synergistic with amphotericin B (AMB) against 19 out of 22 yeast species tested, and synergy was unaffected by iron saturation but was affected by the extent of LF digestion. LF-AMB combination therapy significantly prolonged the survival of Galleria mellonella wax moth larvae infected with Candida albicans or Cryptococcus neoformans and decreased the fungal burden 12- to 25-fold. Evidence that LF directly interacts with the fungal cell surface was seen via scanning electron microscopy, which showed pore formation, hyphal thinning, and major cell collapse in response to LF-AMB synergy. Important virulence mechanisms were disrupted by LF-AMB treatment, which significantly prevented biofilms in C. albicans and C. glabrata, inhibited hyphal development in C. albicans, and reduced cell and capsule size and phenotypic diversity in Cryptococcus Our results demonstrate the potential of LF-AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with the synergy being attributed to the presence of one or more LF peptides.
Highlights
Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens
The samples differed in appearance and other properties: in solid form, LF from Sigma-Aldrich (LF-S) was flaky, while the LFs from dairies (LF from dairy 1 [LF-D1] and LF from dairy 2 [LF-D2]) were powdery, and in solution at 5%, LF-S was more red in color than LF-D1 and LF-D2, indicating a higher iron saturation (Fig. 1A)
While other studies have reported a wide range of activities for LF in the same or similar species (e.g., MICs ranging from 200 to Ͼ6,400 g/ml for C. albicans across various studies) and large species-specific differences [11], we found the MICs across a variety of yeast species to be within a similar range when using the same LF sample but to vary significantly with different LF samples
Summary
Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. We undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. LF was synergistic with amphotericin B (AMB) against 19 out of 22 yeast species tested, and synergy was unaffected by iron saturation but was affected by the extent of LF digestion. Our results demonstrate the potential of LF-AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with the synergy being attributed to the presence of one or more LF peptides. Studies combining LF with various antifungal drugs, including amphotericin B (AMB), several azoles, and 5-fluorocytosine (5FC) have reported interactions that range from indifferent to synergistic, even with the same combination [7, 12,13,14,15,16]. The activity of LF plus AMB was highly synergistic, including in vivo, and LF in combination with AMB could effectively suppress certain pathogenic mechanisms
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