A complex of 18-membered macrolide antibiotics has been discovered in the fermentation broth of strain AB718C-41. The producing culture, isolated from a soil sample collected in Hamden,Connecticut, was identified as a strain of Dactylosporangium aurantiacum and was designated D. aurantiacum subsp. hamdenensis subsp. nov. The antibiotic complex was produced in a NewBrunswick 150-liter fermentor using a mediumconsisting of glucose, soybean oil, soybean flour, beef extract and inorganic salts. Several of the antibiotics were active against sensitive and multiple antibiotic-resistant strains of pathogenic Gram-positive bacteria.

Determination of the mechanism of action of FK506and cyclosporin A has yielded new molecular targets involved in signal transduction during T cell activation. A commontarget of FK506 and cyclosporin A is inhibition of activation of the NFATtranscription factor, for which a specific binding region is present in the promoter of the IL-2 gene. A reporter gene assay has been used to screen for agents that interfere with this early step in T cell activation. Simple aromatic compoundsthat block NFAT-dependent transcription and showin vitro immunosuppressiveactivity were isolated from the broth and mycelia of two Streptomyces sp. fermentations. The compounds were active at concentrations that were not directly cytotoxic.

The ardeemins are a new family of secondary metabolites produced by submerged fermentation of a fungus which was isolated from a soil sample collected in Brazil. Based on taxonomic studies, the producing culture was identified as Aspergillus fischeri var. brasiliensis strain AB 1826M-35. 5-7V-Acetylardeemin potentiated the cytotoxicity of the anticancer agent vinblastine in multidrug resistant humantumorcells.Multidrug resistance (MDR)is characterized by the development of resistance to several structurally unrelated anticancer agents and is a major cause of failure of cancer chemotherapy. The appearance of a specific glycoprotein, P-170, is generally associated with resistant cells1*. P-170 is a membrane associated glycoprotein thought to actively export cytotoxic compoundssuch as anthracyclines and Vinca alkaloids from resistant tumor cells2). Although several compoundsare knownto reverse MDR, none are used clinically because of adverse side effects3*. In the course of screening for modulators of MDR, we discovered a family of novel compounds which we have called ardeemins. 5-JV-Acetylardeemin appears to be the most efficacious of these compoundsin the reversal of MDR. The compoundsare produced in the fermentation broth of Aspergillus fischeri var. brasiliensis strain AB 1826M-35. This paper describes the taxonomy and the fermentation of the producing microorganism and the biological activity of ardeemin and 5-7V-acetylardeemin. The isolation and structural elucidation of these and other congeners are described in an accompanying publication4*. Materials and Methods MicroorganismsStrain AB1826M-35 was isolated from soil collected in Brazil. A subculture of the microorganism was deposited at

HumanRhinoviruses belong to one of the largest family of positive sense RNAviruses; the Picornaviridae, which includes humanpathogens such as enteroviruses (poliovirus, coxsackeivirus, echovirus

The pacidamycins are a new complex of nucleosidyl-peptide antibiotics with highly specific activity against Pseudomonas aeruginosa. They are produced by Streptomyces coeruleorubidus AB 1 183F-64 which was isolated from a soil sample collected at Offenburg in the FRG. The mature spore masses of the producing organism are greenish gray to blue, and the spore chains are arranged in spirals. After the structures of the pacidamycins were determined, the fermentation medium was supplemented with component amino acids. This resulted in the directed biosynthesis of several members of the complex. The overall antibiotic recovered was increased from 1~2 mg/liter to more than 100 mg/liter through a combination of strain selection, mediummanipulation and amino acid feeding experiments.

A novel antibiotic complex, named the calbistrins, has been discovered in the culture broth of a soil fungus. The producing organism, designated AB1875C-28, was identified as a strain of Penicillium restrictum. Calbistrin A, the most potent of the 4-membered complex, has MICsof 0.78 /zg/ml against Candida albicans. Only poor activity is observed against non-candida yeasts, filamentous fungi and bacteria.

In the course of screening with the mixed lymphocytereaction, a new inhibitor of protein kinase C with immunosuppressive activity was isolated from the fermentation broth and mycelia of Streptomyces sp. AB 1869R-359. Although certain similarities exist, this strain is morphologically and physiologically distinct from other reported producers of staurosporine-related compounds. We have found that this strain produces relatively high levels of staurosporine and the new minor compound MLR-52, which possesses the indolo[2,3-a]carbazole chromophore of staurosporine, but differs in the substitution pattern of the sugar moiety. Their structures have been elucidated by mass and NMRspectra. MLR-52has been shown to inhibit the enzymatic activity of protein kinase C and the murinemixed lymphocytereaction.Staurosporine was originally discovered by Omuraand shown to have modest in vitro antifungal activity and strong hypotensive activity.1} Like manyother antibiotics, staurosporine was rediscovered several years later in a mechanistic-based screen. In 1979, Nishizuka and colleagues described a phospholipid/Ca++ dependent protein kinase (protein kinase C) that was directly activated by diacylglycerol.2) This enzyme was subsequently shown to be the predominant cellular receptor for phorbol esters, and a central role for protein kinase C in signal transduction has been described.3) Following binding of a large class of hormones and other cellular effectors to their individual receptors, phospholipase C is activated resulting in production of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate.4) Diacylglycerols, like phorbol esters, activate protein kinase C which modulates other signal transduction cascades and stimulates cell division during activation of T cells and other model systems.5) Based on the importance of this enzyme for signal transduction and the control of cellular proliferation, a search for agents that inhibit protein kinase C was undertaken. The first potent inhibitor identified was staurosporine,6) which has been found to be a nonspecific inhibitor of protein kinases.7) Since the protein kinases are a large family of enzymes that mediate the response of eukaryotic cells to a wide variety of external stimuli,8) it is not surprising that staurosporine has many biological effects. For example, staurosporine activates macrophages,9) inhibits the neutrophil respiratory burst,10) blocks the proliferative response of T lymphoblasts to mitogens1 1) and is markedly cytotoxic.6) Materials and Methods MicroorganismThe microorganism that produces MLR-52was isolated from a soil sample collected near Dorado, Puerto Rico. The culture is a Streptomyces species which we have designated strain AB 1869R-359. A subculture was deposited with the

Tirandalydigin is a new tetramic acid antibiotic which was discovered in a screen designed to find compounds with activity against pathogenic anaerobic bacteria. It was named tirandalydigin because it possesses structural features that are commonto both tirandamycin and streptolydigin. The producing culture, strain AB1006A-9, is a Streptomyces and was compared to the streptomycetes that synthesize tirandamycin and streptolydigin. It is closely related to the former culture and was named Streptomyces tirandis subsp. umidus. Tirandalydigin has MICs in the range of 0.5 to 32 /^g/ml against manypathogenic anaerobes, streptococci, enterococci and legionellae.