Polyene antibiotic that inhibits membrane transport proteins

Abstract

The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

“…Such interactions can compromise membrane integrity and inhibit the function of membrane proteins (19,20). Recent studies suggest that ergosterol sequestration into extracellular aggregates may be the dominant mechanism of action (21,22), although several polyenes, including nystatin and amphotericin B, have also long been known to permeabilize membranes by the formation of ergosterol-dependent transmembrane channels (23).…”

The effect of natamycin on the transcriptome of conidia of Aspergillus niger

“…Recently, it has been shown that natamycin also blocks growth of yeast and fungi via inhibition of amino acid and glucose transport across the plasma membrane (te Welscher et al 2012). In agreement, an up-regulation of transport proteins is observed when conidia are exposed to natamycin.…”

“…Moreover, natamycin interferes with vacuole fusion in yeast cells as well as filamentous fungi (Te Welscher et al 2010). Very recent work has shown that natamycin also reversibly inhibits transport of different nutrient molecules into the cell (Te Welscher et al 2012). …”

<i>In vivo</i> study of antifungal effects of low-molecular-weight chitosan against <i>Candida albicans </i>

“…Nystatin binds to ergosterol within the cell membrane of Candida and creates pores in the fungal cell membrane, resulting in leakage of fungal cell contents and potassium ions, which results in cell death (7,12,13). Polyenes are not absorbed from the gastrointestinal tract, and drug-induced resistance is extremely rare (9,12). However, topical use of nystatin produces an unpleasant taste in the mouth and, if swallowed, can cause symptoms such as nausea, vomiting, and diarrhea.…”

“…Polyene agents such as nystatin and amphotericin are remedial treatments for primary oral candidosis (1,9,11). Nystatin binds to ergosterol within the cell membrane of Candida and creates pores in the fungal cell membrane, resulting in leakage of fungal cell contents and potassium ions, which results in cell death (7,12,13). Polyenes are not absorbed from the gastrointestinal tract, and drug-induced resistance is extremely rare (9,12).…”