DESCRIPTIONS OF ANTIBIOTICS 



227 



Caii(li<IiM 



Produced by: Streptoniyces viridoflavus. 



Synonyins: Originalh' the confusing designations 

 candidin A and candidin B referred to different 

 salt forms of the basic candidin molecule. Candi- 

 din may exist as different salt forms, depending on 

 the pH of isolation. 



Method of extraction: Whole l)roth mixed with 

 Hyflo Super-Cel, adjusted to pH 4.8 with dilute 

 acid to precipitate the colloidally suspended can- 

 didin, and the whole filtered. Solids extracted with 

 butanol-methanol (4:1), water added until separa- 

 tion into phases begins, and pH adjusted to 7.0 

 with NH4OH. Organic pha.se concentrated //( vacuo 

 at low temperature vmtil precipitate forms. A 

 pyridine-glacial acetic acid (10:1) solution of this 

 precipitate is heated to 50°C, warm water added, 

 and the whole cooled. Precipitate which forms is 

 washed with acetone and crystallized from 90 per 

 3ent aqueous dioxane (8). 



Chemical and physical properties: Amphoteric, 

 conjugated heptaene macrolide. Rosettes (from 

 aqueous dioxane) or needles. No melting point; 

 decomposes at >180°C. Soluble in dimethylfor- 

 mamide, pyridine, and dimethyl sulfoxide. Less 

 soluble in glacial acetic acid. Slightly soluble in 

 methanol, 70 per cent 1-propanol, water-saturated 

 butanol, and 90 per cent dioxane. Nearly or com- 

 pletely insoluble in ethanol, butanol, t-butanol, 

 dioxane, toluene, petroleum ether, sodium car- 

 bonate, and water. Ultraviolet absorption spec- 

 trum maxima at 365, 385 (^^I'cm 1600), and 408 m^ 

 (alcohols). Shows a reflectance peak at 340 n\fi in 

 water suspension, a characteristic shared only by 

 amphotericin B among the better known hep- 

 taenes. Infrared spectrimi given in reference 5. 

 [a]'^ = +363°C (c = 0.3 per cent in dimethyl- 

 formamide), or +205° (c = 0.3 per cent in glacial 

 acetic acid). Positive bromine, KMn04 , ninhy- 

 drin, antimony trichloride, and sulfuric acid 

 chromophore (deep blue) tests. Negative ninhy- 

 drin (after hydrolysis), semicarbazide, Benedict, 

 Fehling, Tollen, Schiff, 2,4-dinitrophenylhydra- 

 zine, FeChi . and pine splint tests. Can be differ- 

 entiated by paper chromatography and by bio- 

 logical assay from the other well known heptaene 

 antibiotics (candicidin, ascosin, trichomycin, and 

 amphotericin B). Photo-, thermo-, and acid-labile. 

 Most stable at neutral and alkaline pH. Stable in 

 drj^ form at low temperatures vuider Nj . C46H7.3 

 OieN. Molecular w^eight 895. C = {\().(W; ; H = 

 9.76%; N = 1.65%. Contains four methyl groups, 

 one primary' amino group, and one carboxyl group. 

 Acid degradation products include mycosamine. 

 Lactone contains a series of secondary and ter- 



tiary hydroxyl groups. N -acetylcandidi n,: m.p. 

 159-161°C. N -acetylcandidi n, brucine salt: m.p. 

 107-168°C. Hydrocandidins are biologically inac- 

 tive (1, 3-5, 8, 9). 



Biological activity: Active on yeasts and fila- 

 mentous fungi, including plant pathogens. Com- 

 pletely suppresses all fungi in the fecal flora of 

 mice dosed orally, with a concomitant 1000-fold 

 increase in bacterial count. Active in mice with 

 Histoplasma capsulatiun and C. albicans infec- 

 tions. Most active on solid media at an alkaline 

 pH (about 8.0). N -acetylcandidi n: one-tenth as 

 active as candidin (1, 3, 4, 6, 9). 



Toxicity: LDoo (mice) 7 to 36 mg per kg intra- 

 peritoneally, 1.5 mg per kg intravenously, and 30 

 mg per kg subcutaneously (with necrosis at injec- 

 tion site). Splenic atrophy observed after oral ad- 

 ministration of 100 mg per kg to mice (1, 3). 



References: 



1. Taber, W. et al. Antibiotics & Chemother- 



apy 4: 455-461, 1954. 



2. Taber, W. and Vining, L. C. Bacteriol. 



Proc. 86, 1954. 



3. Vining, L. C. et al. Antibiotics Ann. 980- 



987, 1954-1955. 



4. Oroshnik, W. et al. Science 121: 147-149, 



1955. 



5. \'ining, L. C. and Taber, W. A. Can. J. 



Chem. ;U: 1163-1167, 1956. 



6. Muller. W. H. Am. J. Botany 45: 183-190, 



1958. 



7. Solotorovsk\'. M. et al. Antibiotics & 



Chemotherapy 8:304-371, 1958. 



8. Borowski, E. Personal communication, 



1959. 



9. Lechevalier, H. unpublished data. 



Candiniycin 



Produced by: Strepto)n.yces echiniensis (1). 



Synonyms: Closely related to ascosin and candi- 

 cidin (1). 



Method of extraction: Extracted from broth and 

 mycelium; purification by chromatography (1). 



Chemical and physical properties: Yellow. Sol- 

 uble in aciueous acetone, alcohol, glycol, and dilute 

 NaOH. Less soluble in water. Insoluble in ether, 

 benzol, acetone, and chloroform. Contains no 

 S or halogen. C = 57.17%; H = 8.18%; N = 1.70%. 

 Negative FeCU , ninhydrin, Molisch, Fehling 

 (cold), and Sakaguchi tests. Silver mirror test 

 positive in hot state. Addition of H2SO4 changes 

 the powder to a blue, then to a violet color. Ultra- 

 violet maxima (methanol) at 362, 382, and 406 m^- 

 Stable to acid and alkali pH (1). 



