226 



DESCRIPTIONS OF ANTIBIOTICS 



Upper phase concentrated, then extracted with 

 bntanol at pH 7.0. Forced into a small volume of 

 water by addition of petroleum ether to butanol 

 (5, 7). II. Broth adjusted to pH 3.5 to 4.0 and 

 filtered with a filter-aid. Cake extracted with 

 water-saturated n-butanol. Extract washed with 

 0.333 M NaHCOs , then with water at pH 7.0; 

 pentane added to separate out an aqueous layer. 

 To this aqueous layer are added aqueous washes 

 of the remaining butanol-pentane layer, and the 

 combined aqueous extracts are concentrated in 

 vacuo and lyophilized (13). 



Chemical and physical properties: Conjugated 

 heptaene. Crude candicidin: Soluble in butanol, 

 glycerol, benzyl alcohol, ethylene glycol, and 

 ethylene glycol monomethyl ether. Partially sol- 

 uble in water, ethanol, chloroform, and acetone. 

 Insoluble in benzene, petroleum ether, carbon tet- 

 rachloride, xylene, carbon disulfide, ethylene di- 

 chloride, ether, and ethyl acetate (1). Three compo- 

 nents were demonstrated on paper chromatography 

 with Rf values of 0.00, 0.44, and 0.66 [methanol- 

 0.880 (sic; probably specific gravity) ammonia- 

 water, 20:1:4]. N = 1.58 to 2.16%. Nondialyz- 

 able (1, 7). Fraction A. Reddish brown substance. 

 Soluble in water, ethanol, butanol, ethylene gly- 

 col, and ethylene glycol monomethyl ether. In- 

 soluble in acetone (1). Ultraviolet absorption 

 spectra at 340, 360, 380, and 403 mju (ethanol) (5). 

 C = 62.9%; H = 9.6%; N = 4.7%,. At pH 7, with- 

 stands heating for 10 minutes at 60°C (1). Fraction 

 B: Greenish substance. Soluble in butanol, ethyl- 

 ene glycol, and ethylene glycol monomethyl ether. 

 Insoluble in water, ethanol, and acetone (1). Ul- 

 traviolet absorption spectrum maxima at 340, 362, 

 381, and 404 m^ (ethanol) (5). C = 57.8%; H = 

 9.9%; and N = 7.3% (1). Fraction C: Reddish 

 brown substance. Soluble in ethanol, butanol, 

 ethylene glycol, ethylene glycol monomethyl 

 ether, and acetone. Insoluble in water. Ultraviolet 

 absorption spectrum maxima at 358, 379, and 402 

 niM (1). Fractions A and B are different forms of 

 the same compound; A is the sodium salt of B. 

 Fraction C is probably a degradation product of 

 canchcidin. Candicidin contains an aromatic com- 

 ponent in its molecule, and is ninhydrin-positive 

 (with two amino groups). The molecule of candici- 

 din contains mycosamine and p-aminoacetophe- 

 none (14). 



Biological activity: Active mainly on yeasts, but 

 also on certain filamentous fungi, including a 

 variety of plant pathogens. Fractions A and B 

 differ only quantitatively in antifungal activity. 

 Not active on bacteria, actinomycetes (including 

 Nocardia asteroides), or mycobacteria. Fraction C 

 is relatively inactive. A and B are most active at 



pH 7 to 8 (100 times more active than at pH 5 to 

 6). In tissue culture, inhibits pathogenic (yeast) 

 stage of Histoplasvia capsulatum, Cryptococcits 

 neofornians, Candida albicans, and Blastomyces 

 dermatitidis. Protects against wheat and Poa 

 pratensis stem rust (Puccinia graminis) and infec- 

 tions by Cronarti\im rihicola (uredial stage). Some 

 control of snapdragon rust {Puccinia antirrhini) 

 and powder mildew of beans. Excellent control of 

 bean rust (Uromyces phaseoli) and brown rot of 

 peach (Monilinia fructicola) (1-4, 10-12, 15). 



Toxicity: Crude candicidin: LD50 (mice) 663 mg 

 per kg subcutaneousl}-, 79 mg per kg intraperi- 

 toneally. Nontoxic to germination of pea seeds at 

 125 /ig per ml or less (1) . Candicidin A : LDjo (mice) 

 47 to 65 mg per kg intraperitoneally, 277 mg per 

 kg subcutaneously. Necrosis at injection site (sub- 

 cutaneous or intradermal). Conjuctiva of rabbits 

 and oral mucosa (human) not irritated by a 1 per 

 cent solution applied topically. Least inhibitory 

 dose (tissue culture) 20 to 80 jug per ml. Candici- 

 din B: LD50 (mice) 159 mg per kg subcutaneously, 

 53 mg per kg intraperitoneally (1, 2, 4). 



Utilization: Vulvovaginitis (8). Intertriginous: 

 moniliasis (6). 



References: 



1. Lechevalier, H. et al. Mycologia 45: 155- 



171, 1953. 



2. Kligman, A. M. and Lewis, F. S. Proc. Soc. 



Exptl. Biol. Med. 82: 399-404, 1953. 



3. Alcorn, S. J\I. and Ark, P. A. Plant Disease 



Reptr. :38: 705-709, 1954. 



4. Hu, F. et al. Arch. Dermatol. Syphilol. 



70: 1-15, 1954. 



5. Vining, L. C. et al. 8th Congr. intern. 



botan., Paris Vol. prelim. Sect. 24, 106- 

 110, 1954. 



6. Franks, A. G. et al. J. Invest. Dermatol. 



23: 75-76, 1954. 



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



987, 1954-1955. 



8. Fox, J. L. Antibiotic :Med. 1: 349-350, 



1955. 



9. Oroshnik, W. ct al. Science 121: 147-149, 



1955. 



10. Ark, P. A., and Alcorn, S. :\I. Plant Dis- 



ease Reptr. 40: 85-92, 1956. 



11. Lar.sh, H. W. et al. Antibiotics Ann. 918- 



922, 1956-1957. 



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



1958. 



13. Siminoff. P. U. S. Patent 2,872,373, Febru- 



ary 3, 1959. 



14. Borowski, E. Personal communication. 



15. Lechevalier, H. Antibiotics Ann. 614- 



618, 1959-1960. 



