Tuberc Respir Dis.  1975 Mar;22(1):31-47. 10.4046/trd.1975.22.1.31.

Biology of the Polyene Antifungal Antibiotics: Sensitivity and Resistance

• KMID: 2529001
• DOI: http://doi.org/10.4046/trd.1975.22.1.31

Abstract

Polyene antibiotics are toxic towards eukaryotic cells such as fungi, algae, protozoa, and mammalian cells, but not toxic towards prokaryotic cells such as bacteria. It is now generally accepted that the polyene molecules combine with membrane sterols to yield a complex, as a result of which the cell membrane can no longer function as a selective restraning barrier. Damage to the membrane results in a cell death due to a leakage of many cell constituents. However the mutants insensitive to the polyene antibiotics are occasionally isolated from sensitive strains of many fungi both in vivo and in vitro. Mutants of Aspergillus funnelliae resistant to relatively high level of amphotericin B and low level of nystatin, obtained by successive transfers of wild type in the presence of increasing concentrations of the polyenes, showed quantitatively and qualitatively altered sterol compositions, as compared with that of wild types. Former mutant produced a large amount of Δ^7,22,24(28)-ergostatrien- 3β -01 and a lesser amount of Δ^7,22-ergostadien- 3β -01 while the latter mutant pro duced not only these two sterols but also ergosterol, which is a major sterol of wild types. This phenomenon has also been demonstrated in the polyene resistant musa nts of Cryptococcus neoformans whose sterol compositions are different according to the level of resistance to the polyenes_ While the high level resistant m utants prod uced Δ^{5, 8, 22}-ergostatrien-- 3β -01 and Δ⁸-ergosten- 3β -01 the low level resistant mutants produced Δ^7,22-ergostadien- 3β -01 and Δ7-ergosten-- 3β -01. These results suggest that the effectiveness of polyene bindings is in the order: Δ^5,7, Δ⁷, and Δ⁸-sterol. This order also seems to be true to the impairments of many other properties, relevant to sterols, of both fungi. However as the mutants resistant to amphotericin B of C. neoformans are exclusive from those mutants due to the altered sterol compositions of the cells, the sterol change is not an only mechanism of resistance to the polyenes.