Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolm and its open acid form, mevinolinic acid, were determined by a combination of physical techniques.

The avermectins are a complex of chemically related agents which exhibit extraordinarily potent anthelmintic activity. They are produced by a novel species of actinomycete, NRRL 8165, which we have named Streptomyces avermitilis . The morphological and cultural characteristics which differentiate the producing organism from other species are described. The avermectins have been identified as a series of macrocyclic lactone derivatives which, in contrast to the macrolide or polyene antibiotics, lack significant antibacterial or antifungal activity. The avermectin complex is fully active against the gastrointestinal nematode Nematospiroides dubius when fed to infected mice for 6 days at 0.0002% of the diet. Fermentation development, including medium modification and strain selection, resulted in increasing the broth yields from 9 to 500 μg/ml.

The avermectins, a family of new anthelmintic agents, were isolated from the mycelia of Streptomyces avermitilis. Four closely related major components and four homologous minor components were separated from the complex. Solvent extraction, solvent partition, and adsorption methods were used to isolate and purify the complex; novel partition chromatography systems using Sephadex LH-20 were used to separate the components. A reverse-phase high-pressure liquid chromatography assay for the quantitative determination of all components was used extensively to monitor the purification methods.The avernectin complex, a family of new anthelmintic agents, is produced by fermentation of Streptomyces avermitilis (NRRL 8165), as described in a separate publication (1).The complex contains four closely related major components, Ala, A2a, Bia, and B2a, in varying proportions and four minor components, Alb, A2b, Blb, and B2b, each of which is a lower homolog ofthe corresponding major component. The structures and physicochemical properties of all components are the subject of a separate publication (G. Soc., in press).In this report, the isolation of the complex from broth, the separation of all of its components, and the chromatographic properties of each will be described. For the sake of simplicity, mixtures of homologs will be designated by omis- B2a, 6.74; A2b, 7.22; A2s, 8.00; B,I, 8.32; B,I., 9.70; Al,b, 11.06; and A,,, 11.78. The UV monitor was set at 246 nm to improve the resolution of a major impurity which exhibited a UV maximum at a lower wavelength. Although the UV maximum for avermectins occurred at 245 nm, sensitivity was only slightly reduced at 246 nm, whereas the sensitivity for the impurity was reduced substantially. The UV spectrum of B21 is given in Fig. 1 and is characteristic of all components. Recordings of high-pressure liquid chromatography (HPLC) assays of standard and unknown solutions are given in Fig. 2. RESULTSIsolation of avermectin complex. Approximately 8,000 liters of fermentation broth was filtered, and the cake was washed with water. The wet cake was then slurried in 3,000 liters of acetone, filtered, and washed with 400 liters of 80% acetone. The cake was discarded, and the combined extract and wash were concentrated to 800 liters. The concentrate was adjusted to pH 5 with dilute HCl and then extracted twice with 800-liter portions of methylene chloride.

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Difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters were discovered in fermentation broths of each of two strains of Bacillus subtilis: ATCC 39320 and ATCC39374. Difficidin and oxydifficidin each showed a broad spectrum of activity against aerobic and anaerobic bacteria. Manyof the susceptible aerobes and anaerobes were humanpathogens resistant to one or more antibiotics. Difficidin and oxydifficidin when administered intraperitoneally protected mice against an otherwise lethal bacteremia caused by Klebsiella pneumoniae (ED50 in mg/kg of 1.31 and 15.6 respectively).Neither difficidin nor oxydifficidin were effective when administered via the subcutaneous route.In the course of screening for new antibiotics, difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters0, (Fig. 1)

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In screening for newantifungal agents from fungi, a new lipopeptide antifungal agent, L-671,329, similar to echinocandin B, has been isolated from Zalerion arboricola. Studies indicate that L-671 ,329 is produced under both solid and liquid fermentation conditions. Echinocandins/aculeacins are lipopeptide antifungal agents. The polar, cyclic hexapeptide portion of these compoundsis structurally unusual in that all the amino acids contain one or more hydroxyl groups. In sharp contrast to the peptide portion is the extremely non-polar, fatty side chain, which is amide-linked to the amino group of an ornithine-derived amino acid residue^. Variation has been observed in both the cyclic peptide (hydroxylation and amino acid substitution patterns)2'^and in the lipophilic side chain (length, branching, and degrees of unsaturation)3>4).The antibiotic activity of echinocandins appears to be limited to yeasts, especially Candida sp.5). While both natural2~4) and chemical6) variation of the echinocandin structure have shown that the biological activity can be manipulated via structural modification, enzymatic removal of the fatty side chain has shown that the cyclic peptide is inactive alone7), as is the fatty acid. LY121019, a semisynthetic derivative of echinocandin B which showed good in vitro and in vivo anti-Candida activity, was reported to be at least 20-fold less toxic than amphotericin B and, therefore, promises to be important in treating these types of infections in the clinic8).In this paper the fermentation and isolation of L-671,329, a new echinocandin, will be discussed; in the following papers the structural elucidation9) and biological activities10) of this compound will be described. Materials and MethodsThe methods of detection utilized in the following studies and isolations were antifungal activity as measuredvia zones of inhibition in a disc diffusion assay on agar plates seeded with Candidaalbicans (MY 1028), Merck Culture Collection, HPLCon C18 reversed-phase, or both.Antifungal Assays Seeded agar plates were prepared as follows. Potato dextrose broth (50 ml, Difco) was inoculated with a lyophilized pellet of C. albicans, and the culture was incubated for 24 hours at 28°C, with agitation at 220 rpm. This culture was used as a 1 %inoculum to seed potato dextrose agar (PDA, Difco). Assay samples (20^1) were applied to 6.2 mm-filter discs and air dried at room temperature before being placed on the seeded assay plates. After incubation at 28°C for 24 hours, zones of inhibition were measured via image analysis from the extreme edges of clearing against the background lawn, A standard curve was generated using compoundL-671,329. The critical variation of standard concentrations ranged from 3~8 %.