This is an antifungal drug-mechanism module structured as a biological cascade, not a specific disease. Its nodes are successive steps of the polyene mechanism on the ergosterol membrane (ergosterol-enriched membrane -> polyene binding and ergosterol extraction / pore formation -> membrane permeabilization, ion leakage and oxidative damage -> fungicidal cell death), with an adaptive-escape resistance branch; the polyene drug class (amphotericin B, nystatin) is described in the node text rather than modelled as a separate node. Disorder entries reference individual nodes via conforms_to (e.g., "fungal_membrane_ergosterol_binding#Polyene Binding and Ergosterol Extraction / Pore Formation"), and their polyene treatments point at the inhibited node via target_mechanisms (analogous to how cell-wall-active antibiotic treatments link to "bacterial_cell_wall_synthesis_inhibition#Peptidoglycan Cross-Linking by Penicillin-Binding Proteins"). Key conformance / treatment target: "Polyene Binding and Ergosterol Extraction / Pore Formation" — the sterol-sponge / pore-forming step at which amphotericin B and nystatin engage membrane ergosterol. This module is complementary to the proposed fungal_ergosterol_synthesis_inhibition module — azoles/allylamines block ergosterol synthesis while polyenes bind the finished sterol — so a single fungal disease may conform to both. The resistance node captures the gating knowledge that distinguishes "a polyene is used" from durable activity: rare ergosterol-depletion resistance, plus the imperfect ergosterol-vs-cholesterol selectivity that drives amphotericin B host toxicity. See projects/ANTIFUNGAL.md.
Ergosterol-Enriched Fungal Plasma Membrane
trigger
Ergosterol is the principal sterol of the fungal plasma membrane and the eukaryotic counterpart of mammalian cholesterol, regulating membrane fluidity, microdomain organization, endocytosis, and the function of many membrane proteins. The synthesis and enrichment of ergosterol in the bilayer creates the fungal-specific physical target that polyene antifungals recognize: polyenes bind ergosterol far more avidly than they bind the cholesterol of mammalian membranes, and the conservation of ergosterol as the dominant fungal sterol is what makes the polyene class broad-spectrum across yeasts and molds. This is the upstream trigger of the cascade — the drug-bindable membrane sterol whose presence licenses the entire polyene mechanism.
Downstream
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Polyene Binding and Ergosterol Extraction / Pore Formation
The membrane ergosterol is the substrate that polyene macrolactones bind and extract, initiating the killing mechanism.
Membrane Permeabilization, Ion Leakage and Oxidative Damage
effector
Extraction of ergosterol and the minor pore-forming fraction together breach the integrity of the fungal plasma membrane. Depletion of the sterol disables the many membrane proteins and cellular processes that depend on ergosterol, while the loss of membrane integrity allows leakage of potassium and other ions and is accompanied by oxidative injury. This is the effector step that converts the upstream physical binding event into lethal cellular damage; the same sterol-extracting activity acting on host-cell cholesterol underlies amphotericin B's dose-limiting toxicity.
Downstream
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Fungicidal Cell Death
Loss of membrane integrity, ion leakage, and oxidative damage culminate in osmotic collapse and lysis of the fungal cell.
Fungicidal Cell Death
consequence
The combined sterol depletion and membrane permeabilization are fungicidal rather than merely fungistatic: the fungal plasma membrane is converted to a more crystalline, leaky state and the cell undergoes osmotic collapse and lysis. This fungicidal endpoint — cell killing rather than growth arrest — is the therapeutic consequence of engaging the ergosterol target and is the basis for amphotericin B's role in severe, disseminated, and life-threatening mycoses (with nystatin used topically).
Polyene Resistance via Reduced Membrane Ergosterol
adaptive escape
Because polyenes recognize the membrane sterol rather than a mutable enzyme active site, clinically significant resistance is uncommon — the drug would have to select against the cell's entire ergosterol-dependent membrane biology, a high genetic barrier. When polyene resistance does arise, it is typically through reduced membrane ergosterol content: loss-of-function changes in the ERG ergosterol-biosynthesis pathway (e.g. ERG2, ERG3, ERG6, ERG11) cause the fungus to accumulate alternative sterols/precursors that polyenes bind poorly, so there is less drug-bindable target in the membrane. This trade-off usually impairs membrane fitness and virulence, which is part of why such resistance is rare in the clinic. This adaptive-escape branch off the binding/extraction node documents the gating knowledge that distinguishes "a polyene is being used" from durable activity and explains why polyene resistance, when present, often co-occurs with susceptibility shifts at the ergosterol-synthesis (azole) target.