The Ion Permeability Induced in Thin Lipid Membranes by the Polyene Antibiotics Nystatin and Amphotericin B

Abstract

Characteristics of nystatin and amphotericin B action on thin (< 100 A) lipid membranes are: (a) micromolar amounts increase membrane conductance from 10-8 to over 10-2 -l cm-2 ; (b) such membranes are (nonideally) anion selective and discriminate among anions on the basis of size; (c) membrane sterol is required for action; (d) antibiotic presence on both sides of membrane strongly favors action; (e) conductance is proportional to a large power of antibiotic concentration; (f) conductance decreases -10 times for a 10°C temperature rise; (g) kinetics of antibiotic action are also very temperature sensitive; (h) ion selectivity is pH independent between 3 and 10, but (i) activity is reversibly lost at high pH; (j) methyl ester derivatives are fully active; N-acetyl and N-succinyl derivatives are inactive; (k) current-voltage characteristic is nonlinear when membrane separates nonidentical salt solutions. These characteristics are contrasted with those of valinomycin. Observations (a)-(g) suggest that aggregates of polyene and sterol from opposite sides of the membrane interact to create aqueous pores; these pores are not static, but break up (melt) and reform continuously. Mechanism of anion selectivity is obscure. Observations (h)-(j) suggest-NH, + is important for activity; it is probably not responsible for selectivity, particularly since four polyene antibiotics, each containing two -NH 3 + groups, induce ideal cation selectivity. Possibly the many hydroxyl groups in nystatin and amphotericin B are responsible for anion selectivity. The effects of polyene antibiotics on thin lipid membranes are consistent with their action on biological membranes.

Controlled delivery of membrane proteins to artificial lipid bilayers by nystatin–ergosterol modulated vesicle fusion

“…8d ) is characterised by a slope conductance of 4972 pS and 26572 pS for the low-conductance and high-conductance states, respectively. The reversal potential for both states is +16 mV, indicating that the channel is weakly anion selective, as previously observed for nystatin-cholesterol channels [32,33]. Current trace of a planar bilayer of POPE/POPC (7:3 molar ratio) voltage clamped at +65 mV.…”

“…1). Barrel-like oligomers of polyene macrolides, such as nystatin and amphotericin B, form weakly anionselective channels in the presence of membrane sterols [32][33][34][35][36], with the largest conductances obtained in the presence of ergosterol [37][38][39][40]. Woodbury and Miller exploited the dependence of nystatin channel activity on the presence of a membrane sterol by incorporating the membrane protein of interest into ergosterol-rich vesicles containing nystatin, while using an ergosterol-free planar lipid bilayer.…”

A New Channel-forming Antibiotic from Streptomyces coelicolor A3(2) Which Requires Calcium for its Activity

“…gramicidin A (Hladky & Haydon, 1972), monazomycin (Bamberg & Janko, 1976) and alamethicin (Eisenberg et al, 1963), while others are anion-selective and cholesteroldependent, e.g. nystatin (Cass et al, 1970) and amphotericin B (Ermishkin et al, 1977).…”

“…The most obvious explanation for the observed dependence of conductance on concentration is that the exponent represents the number of monomers interacting to form a conducting unit, as has been suggested for the polyene antibiotics (Finkelstein & Cass, 1968), gramicidin A (Veatch et aZ., 1975) and many other carrier-type antibiotics. Such an explanation, attractive as it might seem, needs to be regarded cautiously in the light of the fact that co-operative (Cass et al, 1970) and other effects (Lea & Croghan, 1969;McLaughlin, 1972) between conducting units or subunits may influence their interpretation. Until detailed studies have been made of random fluctuations of current under voltage clamp, these suggestions remain speculative.…”

Compounds active against cell walls of medically important fungi

“…The aforementioned compounds share a target in that they all interfere with the structural integrity of the fungal cytoplasmic membrane: amphotericin B by physical disruption of the membrane, and azoles by blocking synthesis of the ergosterol component (1,44,255). Even the allylamines, a new class of agent recently introduced to the market, share this target by interfering with squalene epoxidase activity (204).…”