Candicidin and Other Polyenic Antifungal Antibiotics a Review *
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Bull. Org. mond. Sante 1965, 33, 219-226 Bull. Wid Hith Org. Candicidin and Other Polyenic Antifungal Antibiotics A Review * SELMAN A. WAKSMAN 1, HUBERT A. LECHEVALIER2 & CARL P. SCHAFFNER8 About 50 polyenic antifungal antibiotics produced by actinomycetes have been isolated and described. Among these are the most effective antimonilial agents so far known. These polyenes can be classified into four broad groups depending on the number of conjugated carbon-to-carbon double bonds that are present in their chromophores. Only some of the tetraenes (four conjugated double bonds), such as nystatin andpimaricin, and a few heptaenes (seven conjugated double bonds), such as amphotericin B, Trichomycin candicidin and hamycin, have found practical application in the treatment of infectious diseases caused by fungi. Nystatin and pimaricin show the least in vitro activity against fungi, while trichomycin and candicidin are the most active. Recent clinical investigations carried out in the USA have shown that candicidin is very effective in the treatment of vaginal monilial infections. In 1952, two of us in collaboration with two other substances can be divided into a number of groups members of the laboratory of the senior author of substances, the most important of which are the prepared for the Bulletin of the World Health polyenes. This group includes four subgroups: Organization a summary of what was then known the tetraenes, the pentaenes, the hexaenes, and the about antifungal antibiotics (Waksman et al., 1952). heptaenes. With the exception of nystatin, which is At that time, we suggested that two groups of such a tetraene, all the important antifungal polyenic substances could be recognized-namely, those agents from actinomycetes that have found practical that were active agai-nst fungi and bacteria and those application belong to the heptaenes. These are also that were active against fungi only. Of all the anti- the most frequently produced polyenes (Pledger & biotic-producing microbes, the actinomycetes were Lechevalier, 1956; Vanek et al., 1958; Oroshnik & shown to offer the greatest potentialities as sources Mebane, 1963). of antifungal agents. Six of the antibiotics listed The isolation of large numbers of antifungal were studied in further detail: fungicidin (now known antibiotics was made possible through various as nystatin), fradicin, cycloheximide (Actidione), screening programmes, using one or more fungi as antimycin A, and two numbered preparations, test organisms. Schatz & Hazen reported in 1948 C381 and C135. Antibiotic C135 was later named that, out of 243 cultures of actinomycetes isolated candicidin (Lechevalier et al., 1953). None of these from various soils, 124 (51 %) were antagonistic to preparations inhibited bacteria or actinomycetes, one or more of the following fungi: Candida albicans, but they exerted a marked effect upon the growth Cryptococcus neoformans, Trichophyton gypseum, of fungi, especially yeast forms. and T. rubrum. Ball et al. (1957) carried out an During the past fourteen years, an extensive extensive screening programme for antifungal literature has accumulated on the production of antibiotics, using soils collected from all parts of antifungal antibiotics by actinomycetes.4 These the world; the ratio of polyenic to non-polyenic antibiotics was 20: 1. * From the Institute of Microbiology, Rutgers-The State University of New Jersey, New Brunswick, N.J., USA. 1 Professor Emeritus, Microbiologist. POLYENES ' Associate Professor, Microbiologist. ' Associate Professor, Chemist. With the exceptions of griseofulvin and variotin, ' The literature on this subject has been extensively are all the reviewed by Waksman & Lechevalier (1962), Waksman (1963) which produced by fungi, nearly important and kehiek (1964). antifungal antibiotics are produced by actinomycetes 1638 -219- 220 S. A. WAKSMAN, H. A. LECHEVALIER & C. P. SCHAFFNER and are polyenic in nature. Among the important pentamycin, filipin, lagosin, moldcidin, and aliomy- non-polyenic products, one should mention cyclo- cin. None of these has so far found any practical heximide, an actinomycetic product mainly used application. against plant pathogens. The polyenes possess similar chemical properties (Drouhet, 1958), but they can be largely distin- Hexaenes guished by their characteristic light-absorption Flavacid was the first hexaene obtained from a spectra. This is due to the presence in the molecule culture of Streptomyces flavus (Takahashi, 1953). of a series of conjugated unsaturated double bonds Among the other known hexaenes, one may mention (Oroshnik et al., 1955). They are unstable com- mediocidin, endomycin, and cryptocidin. None of pounds, especially in the light and in acidic or them has been highly purified and none has found alkaline solutions. They are not readily soluble in practical application. non-polar solvents or in water. Their high activity upon pathogenic yeasts and yeast-like fungi tended to render these antibiotics extremely valuable in Heptaenes the treatment of various fungal infections in man This group of polyenic antibiotics contains some and in animals not otherwise subject to therapy. of the most important antifungal agents that have The recent extensive use of tetracyclines in human found application in human and animal therapy. and animal therapy tends to favour moniliasis and Candicidin, Trichomycin and ascosin were the other infections due to yeast-like fungi. This further earliest reported. Later amphotericin B and candi- necessitated the use of polyenes for the treatment of din, and, more recently, hamycin were isolated and such secondary infections. The polyenes are usually found to be highly effective. A number of other produced by cultures of actinomycetes, some of heptaenes have been isolated, such as perimycin, which also form other antibiotics. heptamycin and various others, designated by letter Nearly 50 polyene antibiotics have now been or by number. isolated, many of which have been crystallized. On The candicidin-producing culture (a strain of the basis of their absorption of light, they are usually Streptomyces griseus) was first isolated in 1948 from separated into four major subgroups, based upon a sample of cow manure (Lechevalier et al., 1953). the presence of a chain of four, five, six or seven An antibiotic preparation obtained from this culture conjugated double bonds. Their chemical and (C135) was highly active upon yeasts and yeast-like biological properties have been summarized in fungi, but not upon filamentous fungi, and had no various reports (Neelameghan, 1960; Vining, 1960; activity upon bacteria. It was named candicidin Drouhet, 1963). because of its high activity on Candida albicans. Candicidin was found to be similar, in its light- Tetraenes absorption spectrum, to ascosin, but was quite Fungicidin, later designated as nystatin, is a distinct from nystatin, antimycoin, chromin, and tetraene. It was the first polyenic antibiotic isolated rimocidin. Further studies (Vining et al., 1954) (Hazen & Brown, 1950) from a culture of Strepto- brought out the fact that candicidin was closely myces noursei. It found extensive practical applica- related to ascosin (Hickey et al., 1952), and tricho- tion in the treatment of monilial and other infections mycin (Hosoya et al., 1952). Another antibiotic, caused by yeast-like fungi (Dutcher, 1957; Lampen, candidin (Vining et al., 1955), also isolated in our 1962). Other tetraene antibiotics later isolated laboratory, differed from the ascosin-candicidin- include rimocidin, chromin, antimycoin, sistomy- Trichomycin type. A comparison of four polyenes cosin, pimaricin, etruscomycin, unamycin, protoci- pointed to a very high activity of candicidin (see dine, and akitamycin. None of these has found, so the table). far as is known, any practical application. These four polyenes, when tested on a solid medium, were more active against growing fungi at Pentaenes a neutral pH than at an acid pH. In a liquid medium, Eurocidin was probably the first pentaene isolated differences in activity at various pH values were (Nakazawa, 1955) from actinomycete cultures. less striking. The activity of candicidin varied with Among the other pentaenes now known, mention pH more than that of the other three polyenes. may be made of fungichromin, fungichromatin, Nystatin was least affected by pH variations. CANDICIDIN AND OTHER POLYBNIC ANTIFUNGAL ANTIBIOTICS 221 EFFECT OF FOUR POLYENIC ANTIFUNGAL ANTIBIOTICS AT TWO DIFFERENT pH VALUES a Minimum Inhibitory concentration b (<g/mI) AntUbIotic C. albkans S. cerevislae A. niger pH 4.5 pH 7.0 Rati pH4.5/0 pH 4.5 pH 7.0 pH 4.5 pH 7.0 Nystatin 4.5 1.6 2.8 5.7 1.7 Candidin 0.5 0.12 4.2 0.40 0.11 Amphotericin B 0.5 0.15 3.3 0.43 0.09 Candicidin 0.057 0.005 11.5 0.025 0.001 0.7 0.1 a Reproduced, by permisslon, from Lechevaller (1960). b Average of three assays. IN VIVO ACTIVITIES OF POLYENE ANTIBIOTICS Fungimycin (syn. perimycin) was isolated in 1952 in crude form by Wooldridge and Hoffmann from a The polyenes conform to a general pattern of culture later designated as S. coelicolor var. amino- toxicity and antimicrobial activity, exhibiting varying philus. Further chemical investigations (Borowski degrees of action against many species of fungi et al., 1960) showed it to be a unique member of the (Gerke & Madigan, 1961). They have no effect upon aromatic subgroup of heptaene antibiotics. the growth of bacteria, but in some cases they are active against certain protozoa (Furtado, 1960). Amphotericin was isolated (Gold et