Amphotericin B:30 years of clin-ical experience[J].

Exposure of the yeast Candida albicans to the macrolide antibiotic erythromycin (C37H67NO13) results in elevated tolerance to the polyene antifungal amphotericin e. Erythromycin displays no fungistatic activity against C. albicans but inhibits the synthesis of cytochromes, particularly cytochrome aa(3). Consequently there is a reduction in aerobic respiration by up to 90% when cells are exposed to 10 mg mL(-1) erythromycin. Cellular ergosterol levels are also severely reduced. Erythromycin inhibits protein biosynthesis in ribosomes (mitoribosomes) located within the mitochondrion of the yeast cell, which results in a disruption of cytochrome biosynthesis with an adverse effect on respiration. The synthesis of ergosterol is oxygen dependent and consequently ergosterol levels are depleted in erythromycin-treated C. albicans. Ergosterol is the target for amphotericin B and since there is less of this sterol in erythromycin-treated cells, there is an increase in tolerance of the antifungal agent. Our work indicates that co- administration of erythromycin and amphotericin B to control bacterial and fungal infections, respectively, may inadvertently lead to an elevation in the tolerance of C. albicans for this antifungal agent.

Amphotericin-B-mediated reactivation of latent HIV-1 infection[J].

Researches on the gene clusters of amphotericin B and its combinatorial biology[J].

Renal effects of amphotericin B lipid complex[J].

Since deletion of only two genes in the sphingolipid biosynthetic pathway sensitized cells to AmB, we tested the effects on AmB resistance of chemical inhibition of sphingolipid biosynthesis in wild-type strains. Myriocin is a specific inhibitor of serine palmitoyltransferase encoded by the essential genes LCB1 and LCB2, which catalyze the first committed step of sphingolipid biosynthesis (, ). We incubated C. albicans (SC5314), C. glabrata (CG462), C. lusitaniae (CL1 and CL6), and S. cerevisiae (FY4 and BY4743) strains at different concentrations of AmB and myriocin, alone and in combination. Myriocin at a sublethal concentration (0.4 μg/ml) rendered the cells sensitive to sublethal concentrations of AmB (0.1 μg/ml for C. albicans, S. cerevisiae, and C. lusitaniae strain CL1 and 0.25 μg/ml for C. glabrata and C. lusitaniae strain CL6), indicating that inhibition of sphingolipid biosynthesis sensitizes cells to AmB (). To quantitate this, a checkerboard broth microdilution assay using a CLSI standard reference method () was used. Myriocin sensitized cells to AmB by 4- to 8-fold and was synergistic with AmB for all the tested strains, with a fractional inhibitory concentration (FIC) index of ). However, the synergistic effect of myriocin remains to be verified with other pathogenic Candida species. To confirm if AmB sensitivity is due to depletion of sphingolipids, we supplemented AmB-myriocin plates with a sublethal concentration (10 μM) of phytosphingosine (PHS). PHS is an intermediate downstream of serine palmitoyltransferase in sphingolipid biosynthesis, and it is known to rescue myriocin inhibition of sphingolipid biosynthesis (). We found that PHS reversed the AmB sensitivity of myriocin-treated cells, confirming the role of sphingolipids in AmB resistance ().

Biosynthesis of amphotericin B[J].

In recent years, with the development of AmB derivatives, the analysis of genome of the and the metabolic pathways of AmB, more and more strategies involving genetic engineering and metabolic engineering were used to study the combinatorial biosynthesis of AmB.

Involvement of ABC transporter genes slnTI and slnTⅡ in salinomycin biosynthesis[J].
Quantitative structure-activi-ty relationships in amphotericin B derivatives[J].

Disruption of Ergosterol Biosynthesis Confers Resistance ..

Deletants of the sphingolipid biosynthetic pathway genes FEN1 and SUR4 of Saccharomyces cerevisiae, as well as deletants of their orthologs in Candida albicans, were found to be 2- to 5-fold-more sensitive to amphotericin B (AmB) than parent strains. The inhibition of sphingolipid biosynthesis in parent strains by myriocin sensitized them to AmB, which can be reversed by providing phytosphingosine, an intermediate in the sphingolipid pathway. These results indicate that sphingolipids modulate AmB resistance, with implications for mechanisms underlying AmB action and resistance.

Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups[J].

A+ complete biosynthesis of erythromycin a | …

MFAME, N-methylN-D-fructosyl amphotericin B methyl ester, a new amphotericin B de-rivative of low toxicity:relationship between self-association and ef-fects on red blood cells[J].

Engineered biosynthesis of disac-charide-modified polyene macrolides[J].

Amphotericin B selection of mutant Chinese hamster …

From an epidemiological point of view a certain treatment failure percentage in the range of 20% might be acceptable for a primary therapy as long as a viable salvage therapy is available, but as explained, today this is no longer thecase with the combination of Azole class drugs and Amphotericin B, resulting in often desperate situations in which hospitalized patients find an untimely death as a result of insufficient treatment options.