Nystatin and Amphotericin

SEVEN-, EIGHT-MEMBERED AND LARGER HETEROCYCLIC RINGS 

Recently, the recombinant KR domain with putative epimerase activity NysKRl from module 1 of the nystatin PKS was studied, whose stereospecificity can be predicted from both the protein sequence and the product structure KR was incubated with NADPH and 2R)- or (2R5)-2-methyl-3-ketobutanoyl-ACP generated enzymatically in situ or via chemoenzymatic synthesis, respectively. It was observed that NysKRl stereospecifically produced the corresponding (25, 35 )-2-methyl-3-hydroxybutanoyl-ACP in which the 2-methyl substituent had 

Amphotericin B was first isolated from the soil bacterium Streptomyces nodosus obtained from the bed of the Orinoco river in 1955 [140, 141], Its full stereostructure 147 was elucidated in 1970 when an X-ray structure of the A-iodoacetyl derivative was obtained [142], 

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Cass A., Finklestein A. Krespi V. (1970) The ion permeability induced in thin lipid membranes by the polyene antibiotics nystatin and amphotericin B. J Gen Physiol, 56, 100-124. 

Nystatin and amphotericin B, in the presence of sterols, form temporary channels across lipid bilayers. Neutral molecules under the size of glucose can traverse the... 

Nystatin and amphotericin are useful in the topical therapy of C albicans infections but ineffective against dermatophytes. Nystatin is limited to topical treatment of cutaneous and mucosal Candida infections because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration. Amphotericin has a broader antifungal spectrum and is used intravenously in the treatment of many systemic mycoses (see Chapter 48) and to a lesser extent in the treatment of cutaneous Candida infections. 

Macrolides. Antibiotics in the macrolide group are macrocyclic lactones that can be further classified into two main subgroups (I) polyene macrolides that are antifungal agents and include compounds like nystatin and amphotericin B and (2) antibacterial antibiotics represented by erythromycin and tylosin. A number of other subfamilies of antibacterial and antifungal antibiotics fall into the broad category of macrolides,... 

Zotchev SB, Caffrey P (2009) Genetic analysis of nystatin and amphotericin biosynthesis. Methods Enzymol 459 243-258... 

Some peptide antibiotics act as trans-membrane ion channels. Vibrational spectroscopy shows that ionophores, such as gramicidin A, valinomycin, nystatin, and amphotericins, interact with phospholipid bilayers (Susi et al., 1979). 

Vibrational spectroscopy also shows interactions of polyene antibiotic ion channels nystatin and amphotericin B with phospholipid bilayers (Bunow and Lewin, 1977a Iqbal and Weidekamm, 1979 Van de Ven et al., 1984). In particular, Fourier Transform Raman spectroscopy demonstrates that at high temperature, the amphotericin A complex of DPPC/cholesterol is more ordered, whereas the amphotericin B complex is as ordered as the pure lipid/cholesterol system. In the low temperature phase and in the presence of the sterol-antibiotic complex, the bilayers were suggested to be in the interdigitated state (Levin and Neil Lewis, 1990). 

AndreollTE. On the anatomy of amphotericin B-cholesterol pores in lipid bilayer membranes. Kidney Int 1973 4 337-45. DeKruijiff B, Demel RA. Polyene antibiotic-sterol interactions in membranes of Acholeplesma laidlawii cellsand lecithin liposomes. III. Molecular structure of the polyene antibiotic-cholesterol complexes. Biochem Biophys Acta 1974 339 57-70. HoIzRW.Theeffectsofthe polyene antibiotics nystatin and amphotericin Bon thin lipid membranes. Ann N Y Acad Sell 974 235 469-79. 

What concerns us in this review, however, is the fact that those polyenes whidi contain nitrogen yield an amino sugar on acid hydrolysis. Dutcher and coworkers reported the isolation of this new amino sugar, which they named mycosamine, in 1957. The same product was obtained by hydrolysis of nystatin and amphotericin B. Subsequently, mycosamine... 

There is substantial evidence that a number of substances can produce ion-permeable pores in lipid bilayers. These include gramicidin, alamethicin, nystatin and amphotericin B. Their structures are given in Figure 1.1. The structures of these substances are different, gramicidin being a linear pofypeptide whereas alamethicin is a cyclic polypeptide. Nystatin and amphotericin B belong to the class of polyene antibiotics. 

More recently, essentially similar findings to those for gramicidin have been reported for the two polyenes nystatin and amphotericin B [23]. It has long... 

Estimates of the stoichiometry of polyene—sterol complex can be made from differential scanning calorimetry (DSC) of lecithin—sterol dispersions [146]. When the values obtained by DSC [146] were corrected for the amount of cholesterol which would be unavailable for polyene binding [154], it was shown that the number of cholesterol molecules that could be complexed or associated with fllipin, etniscomycin, pimaridn, nystatin and amphotericin B were 1.2,0.6, 1.7, 1.2 and 3.9, respectively. Permeability studies using cholesterol containing A. laidlawii cells [173] indicated a similar stoichiometry (fllipin 0.7, etrusco-mycin, 0.3, nystatin, 1.6 and amphotericin B, 3.3). Measurement of the binding of various polyene antibiotics to cholesterol-containing A. laidlawii membranes also gave an estimate of the number of cholesterol molecules that combine with fllipin, etruscomycin, pimaricin and amphotericin B. The values obtained were 1.2,1.6,1.5 and 0.7, respectively [153]. 

Nystatin and amphotericin B induced a cation-selective conductance when added to one side of a lipid bilayer but induce anion-selective conductance when added to both sides [203]. The antibiotic concentrations required to produce permselective changes on one side of the bilayers were much greater than those required to demonstrate activity when introduced on both sides of the membrane [154,254]. The two-sided effect resulted from the formation of aqueous pores through the bilayer due to the combination of two half pores. The onesided effect resulted from the changes in permeability induced by half pores alone. 

When the aromatic heptaene, candicidin, was added to both sides of a bilayer under similar conditions, a cation-selective pore was produced (in contrast with the anion-selective pore produced by nystatin and amphotericin) [203]. This antibiotic forms a different type of pore, as unlike nystatin or amphotericin B it was equally effective when only added to one side of the membrane [255]. 

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