Polyene Macrolide Antibiotic Research Articles

In vitro anti-mycoplasmal activity of amphotericin B methyl ester.

The polyene macrolide antibiotic amphotericin B (AB) and its chemically modified derivative amphotericin B methyl ester (AME) were tested for in vitro activity against Acholeplasma laidlawii, Spiroplasma citri and Mycoplasma gallisepticum. Both polyene macrolide preparations demonstrated anti-mycoplasmal activity. However, AME was mycoplasmacidal toward all three strains of mycoplasma at levels which previous studies have indicated would be permissible for most cell culture systems, whereas the levels of AB required for similar activity would be physiologically intolerable for tissue culture cells. In addition, AME was 100 fold more active than AB toward A. laidlawii, 10 fold more active than AB toward S. citri and demonstrated equivalent activity as AB toward M gallisepticum. The in vitro anti-mycoplasmal activity of AME and AB was directly correlated with polyene macrolide antibiotic levels and the number of treated mycoplasma.

Polyene antibiotics. VII. Carbon-13 nuclear magnetic resonance evidence for cyclic hemiketals in the polyene antibiotics amphotericin B, nystatin A1, tetrin A, tetrin B, lucensomycin, and pimaricin1,2.

Carbon magnetic resonance establishes conclusively that six polyene macrolide antibiotics containing keto groups (the heptaene amphotericin B, the tetraene-diene nystatin A1, and the tetraenes tetrin A, tetrin B, pimaricin, and lucensomycin) exist in the hemiketal form in solution. Their spectra all contain a hemiketal carbon's absorption near 97 ppm but lack a keto carbon's absorption near 210 ppm. The non-polyenic macrolide erythromycin, on the other hand, exists in the keto form.

Effects of polyene macrolide antibiotics on normal and protoplast type L-form cells of Escherichia coli W1655F+.

The action of the polyene macrolide antibiotics mycotrienin, pimaricin, lucensomycin, tetramycin, rimocidin, nystatin, filipin, lagosin, pentaene antibiotic 2814P, flavomycoin, flavofungin, hexaene antibiotic 5001P, and candicidin, including perhydro derivatives of them, on wall-less stable protoplast type L-form and normal rod form cells of E. coli W1655F+ was studied. No inhibition of the normal rod form cells was detected. In contrast to these results the growth of the L-form cells was inhibited by all of the substances tested, with the exception of pimaricin. Further experiments have shown that the differences in sensitivity of normal and L-form cells cannot be explained by differences in sterol content, the target site of polyene antibiotics in sensitive eukaryotic cells. According to our results it is obvious that the cell wall of the normal cells functions as a penetration barrier to polyene antibiotics.

Sterol and fatty acid composition of polyene macrolide antibiotic resistant Torulopsis glabrata.

Successive reculturing of Torulopsis glabrata on media containing increasing concentration of the polyene macrolide antibiotics nystalin or lucensomycin resulted in the segregation of cultures resistant to these antibiotics. Isolates resistant to lucensomycin showed good resistance to nystatin, and vice versa. Analysis of the sterols and fatty acids of sensitive and polyene resistant T. glabrata revealed that compositional changes occurred in both classes of lipids upon acquistion of resistance. The sterol composition of nystatin and lucensomycin resistant cultures possessed reduced amounts of, or no ergosterol (the major sterol of the sensitive parent culture), and increased amounts of sterols which were biogenetically more primitive than ergosterol. Resistant cultures in which ergosterol was absent possessed a fatty acid composition that did not differ significantly from the parent sensitive culture grown under identical conditions. Resistant cultures containing significantly reduced amounts of ergosterol were found to possess altered fatty acid compositions. Generally it was observed that these latter cultures possessed fatty acids containing shorter and more saturated chains. These results are considered to indicate that alteration in both lipid and sterol composition is involved in determination of culture resistance to polyene macrolides.

Kinetics of biosynthesis of polyene macrolide antibiotics in batch cultures: Cell maturation time

AbstractThe changes in several parameters of the candicidin fermentation (total, mycelium‐associated, and extracellular product formation; growth rate; DNA content; glucose utilization; dissolved oxygen in the broth; and oxygen uptake rate) during the trophophase‐idiophase transition are compared with previously reported data for the polyene macrolides, candidin and candihexin. The maturation time, tm, and the productformation rate constant, kp, have been calculated for each of the three polyene macrolides using a simple mathematical model. Slow‐feeding of glucose, which resulted in candidin and candihexin overproduction has been shown to increase the polyene formation rate constant and toretard trophophase to idiophase transition (longer maturation time). The opposite effect is achieved by repeated feeding of soybean meal. The values of the maturation times and polyene formation rates obtained were used to predict the production of polyene macrolide antibiotics in batch cultures.

Wirkung von Polyen-Makrolidantibiotica auf normale und zellwandlose Zellen vonEscherichia coli W1655F+

The polyene macrolide antibiotics are active against yeast, fungi, and other eukaryotic cells, but are with a few exceptions inactive against bacteria. The resistance of bacteria against these compounds is usually explained by the absence of sterols in their cells, the target sites of polyene antibiotics. However, in our experiments with mycotrienin, nystatin, tetramycin, lucenosmycin, rimocidin, filipin, lagosin, flavofungin, flavomycoin, antibiotic 2814P, antibiotic 5001P, and candicidin it was demonstrated that bacteria may be susceptible to polyene antibiotics, too, if the wall-less stable protoplast type L-form of E. coli W1655F+ is used. The measured growth inhibition concentrations were comparable with those of typical antibacterial antibiotics. Our experiments have shown that the normal rod form and the wall-less L-form of E. coli W1655F+ contain traces of sterols in nearly the same concentration range. This means that the selective sensitivity of the L-form cannot be explained by higher sterol content of these cells in comparison to the resistant normal rod form cells. We assume that the bacterial cell wall is responsible for the resistance of the normal rod form by masking internal target sites.

Stimulatory effect of amphotericin B methyl ester on the grwoth of L-M and Vero cells.

The chemically modified polyene macrolide antibiotic, amphotericin B methyl ester (AME), exhibited a concentration-dependent growth stimulatory effect on established lines of mouse (L-M) and monkey (Vero) cells. Stimulation was indicated by increases in growth rate, and in the enhanced synthesis of DNA and RNA. In contrast, the parental antibiotic amphotericin B and the desoxycholate complex of amphotericin B, FungizoneR, did not elicit a similar proliferative response in L-M or Vero cells. AME was not growth-promoting toward low passage strains of mouse (PMK 6) and monkey cells (MGK 8).

Wirkung von Polyen-Makrolidantibiotica auf normale und zellwandlose Zellen vonEscherichia coliW1655F+

The polyene macrolide antibiotics are active against yeasts, fungi, and other eukaryotic cells, but are with a few exceptions inactive against bacteria. The resistance of bacteria against these compounds is usually explained by the absence of sterols in their cells, the target sites of polyene antibiotics. However, in our experiments with mycotrienin, nystatin, tetramycin, lucensomycin, rimocidin, filipin, lagosin, flavofungin, flavomycoin, antibiotic 2814 P, antibiotic 5001 P, and candicidin it was demonstrated that bacteria may be susceptible to polyene antibiotics, too, if the wall-less stable protoplast type L-form of E. coli W1655F+ is used. The measured growth inhibition concentrations were comparable with those of typical antibacterial antibiotics. Our experiments have shown that the normal rod form and the wall-less L-form of E. coli W1655F+ contain traces of sterols in nearly the same concentration range. This means that the selective sensitivity of the L-form cannot be explained by higher sterol content of these cells in comparison to the resistant normal rod form cells. We assume that the bacterial cell wall is responsible for the resistance of the normal rod form by masking internal target sites.

N-glycosyl derivatives of polyene macrolide antibiotics.

N-glycosyl derivatives of polyene macrolide antibiotics.

The structural elucidation of polyene macrolide antibiotics by mass spectrometry Nystatin, amphotericin B and pimaricin.

Complete mass spectra of the pertimethylsilylated derivatives of three high molecular weight polyene macrolide antibiotics are reported for the first time. The fragmentation pathways which are proposed have been corroborated by the stable isotope derivatives d9-TMS and d3-acetyl. Accurate mass measurements and metastable transitions confirm the proposed fragmentation mechanisms in the low mass range. Nystatin—the macrolide of highest molecular weight in this study—expels several TMSOH molecules and a TMS radical. Amphotericin B underwent extensive rearrangements preliminary to eliminating a series of TMSOH molecules. An apparent equilibrium between the keto and ketal forms of amphotericin B facilitated the rearrangements. Pimaricin fragmented in a manner parallel to that of the other two macrolides. The sugar portion of the molecules dominated the fragmentation in the low mass region in the spectra of all compounds. The transfer of a TMS group from the sugar amine to the glycosidic oxygen was observed when the amino sugar was eliminated from the intact molecule. The resulting sugar ion then expelled ammonia.

Chemistry and biology of the polyene macrolide antibiotics

Chemistry and biology of the polyene macrolide antibiotics

Chemistry and biology of the polyene macrolide antibiotics

Chemistry and biology of the polyene macrolide antibiotics

Chemistry and biology of the polyene macrolide antibiotics.

Chemistry and biology of the polyene macrolide antibiotics.

Chemistry and biology of the polyene macrolide antibiotics.

Chemistry and biology of the polyene macrolide antibiotics.

Studies on blasticidin A.

Blasticidin A (C51-52H99-101O23N1/2Ca, m. p. 165.5-166.5°C, λmax 246 mμ and 298mμ in 50 % methanol, [α]24D-31° in pyridine) was isolated in crystal form as calcium-chelated compound. The antibiotic shows activity against a variety of microorganisms with relatively less toxicity to mice orally. It seems to have some relationship to polyene macrolide antibiotics, but has marked differences in its properties. The isolation, purification and physicochemical properties of the antibiotic are described.

Pimaricin—VII : The absolute configuration at C-25

The absolute configuration at C-25, the lactone forming carbon atom, in the polyene macrolide antibiotic pimaricin has been established as R by isolation of (3 R)-1,3-diacetoxybutane obtained by ozonolysis followed by reductive work-up and acetylation.