A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum.The antibioticproducing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 pg/ml.Its apparent activity against Microsporum gypseum and Trichophyton granulosum is lower because of its instability in culture media on prolonged incubation required by these fungi. No activity was observed against gram-positive and gram-negative bacteria. Acute toxicity in mice is low.Cultures of a streptomycete isolated from an Easter Island (Rapa Nui) soil sample were found to inhibit the yeast, Candida albicans, and the dermatophytes, Microsporum gypseum and Trichophyton granulosum; antibacterial activity was only marginal and limited to some grampositive species, such as Sarcina lutea and Staphylococcus aureus; all gram-negative bacteria tested were resistant. The active principle was isolated from the mycelium of the streptomycete and the crystalline material obtained after purification was found to inhibit mainly Candida albicans; lesser activity was observed against the dermatophytes and no activity was demonstrated against any of the gram-positive and gram-negative bacteria tested. The antibiotic was named rapamycin [Etymol.: Rapa-(Rapa Nui=Easter Island), -mycin]. Its structure is still unknown. This paper deals with the characterization of the producing streptomycete, the isolation and purification of the antibiotic and some of its biological properties. Identification of the Rapamycin-Producing StreptomyceteStreptomycete strain AY B-994 was isolated from a soil sample collected in Easter Island (Rapa Nui): the soil was diluted in distilled water and the resulting suspensions were plated on yeast-starch agar according to the double-layer technique of PORTER et al.".After one week of incubation at 28°C the streptomycete colonies were purified by repeated streaking and the pure strains grown separately on yeast-starch agar plates to yield confluent growth. After 4-,-10 days of incubation, discs (7 mm in diameter) were cut and transferred onto the surface of plates of Bacto-Blood Agar Base (Difco Laboratories, Detroit, Mich.) inoculated with test bacteria and SABOURAUD dextrose agar inoculated with test yeast and dermatophytes.The Blood Agar Base plates were inoculated with a standardized bacterial inoculum grown at 37"C for 5 hours in Bacto-Nutrient broth; the SABOURAUD dextrose agar plates were inoculated with a standardized inoculum consisting of cells of yeast or spores of dermatophytes.Plates were

Rapamycin is a new antifungal antibiotic produced by Streptomyces hygroscopicus

Rapamycin is a triene antibiotic produced by Streptonrvces hygroscopicus1,2). Structure elucidation revealed the presence of a pipecolic acid residue in the macrolide3.4). Several yeasts, as well as yeast-like and filamentous fungi, are sensitive to rapamycin; however, the main feature of the antibiotic is its high activity against Candida albicans (MIC 0.02 ~ 0.20 tcg/ml)5). Nucleic acids synthesis inhibition and degradation in C. albicans are the primary modes of action6). The LD50 ip of rapamycin in the mouse is 587 mg/kg. The antibiotic also has immuno-suppressant activity7) : it is half as potent as cyclophosphamide in inhibiting experimental allergic encephalomyelitis and is as potent as this standard reference drug in preventing adjuvant-induced arthritis. The mode of action and the pharmacological effects warranted the evaluation of rapamycin in experimental tumor models. The National Cancer Institute (NCI, Division of Cancer Treatment) conducted the initial studies and reported modest activity against P388 lymphocytic leukemia (Increased life span (ILS)=30~40% at 1.25 mg/kg) and no activity against L1210 lymphoid leukemia and Lewis lung carcinoma8). Activity was reported against B16 melanocarcinoma (ILS 80% at 100 mg/kg), Colon 26 tumor (ILS 105 % at 6.25 mg/kg) and EM ependymoblastoma (ILS 85 % at 50 mg/kg and ILS 100; at 200 mg/kg). Rapamycin was also active against the solid tumors, CD8F1 mammary tumor (80% tumor weight inhibition at 25 mg/kg) andColon 38 tumor (85% tumor weight inhibition at 25 mg/kg). Subrenal capsule CX-1 colon adenocarcinoma xenograft and spontaneous colon adenocarcinoma 11/A were sensitive to rapamycin.We report here a more detailed evaluation of the efficacy of rapamycin in transplantable tumor models. The effects of dosage, regimen and route of administration were studied. Rapamycin was compared to other antitumor agents; the antineoplastic effects of rapamycin in combination were also evaluated t Ayerst Laboratories , 567 Ridge Road, Princeton, NJ 08852, USA. >t Institut Armand-Frappier , 531, Boulevard des Prairies, Ville de Laval, Que, Canada H7V 1B7.

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The activity of rapamycin, a new anti-Candida antibiotic, was not affected by pH values between 6 and 8; at pH 4, however, activity was abolished. The MIC of rapamycin did not vary drastically with the size of inoculum: a ten-fold dilution of the inoculum reduced the MIC only two-fold. Serum binding was extensive. Serum levels obtained in mice were higher on subcutaneous injection than with oral administration. Dogs absorbed rapamycin after oral administration.Rapamycin cured systemic candidosis in mice: PD50 s. c. was 9.5 mg/kg; PDso p. o. was 11 mg/kg. In the same experimental infections amphotericin B and nystatin exhibited PDso values of <0.25 mg and >4,000 units/kg respectively. Rapamycin and amphotericin B, administered at 1, 4 and 24 hours after infection, gave approximately the same percent survival after 30 days of observation. When the above treatment was extended by an additional daily treatment for 6 days, rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period. Vaginal candidosis in female rats was treated efficiently (91 % cure) by rapamycin administered orally. No increase of resistance of C. albicans was observed during treatment.

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A new antibiotic, naphthyridinomycin, was isolated in crystalline form from the culture filtrate of Streptomyces lusitanus AY B-1026. The antibiotic is active against a large number of both gram-positive and gram-negative bacteria, and inactive against Candida albicans, Trichophyton granulosum and Microsporum gypseum. The antibiotic is toxic in mice. A new strain of streptomycete was isolated from a Easter Island (Rapa Nui) soil sample. Cultures of this microorganism were found to produce marked antibacterial activity and to bring about strong morphological changes in Escherichia coli. The active principle was isolated

A streptomycete was isolated from a Guatemala soil sample and found to inhibit Grampositive bacteria including mycobacteria. The antibiotic-producing microorganism was characterized, identified as a new species and named Streptomyces ravidus. The antibiotic principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named ravidomycin. Ravidomycin is mainly active against Gram-positive bacteria including mycobacteria. It shows only weak activity against Gram-negative organisms and no activity against fungi. Ravidomycin exhibits potent antitumor activity against P388 lymphocytic leukemia, Colon 38 tumor and CD8F1 mammary tumor. Acute toxicity in mice is low.