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Chemobiosynthesis has been used to prepare analogs of erythromycins having unique functional groups at the 15-position. Using diketide thioester feeding to genetically engineered Streptomyces coelicolor, analogs of 6-deoxyerythronolide B were prepared having 15-fluoro, 15-chloro, and 15-azido groups. Bioconversion using a genetically engineered mutant of Saccharopolyspora erythraea was used to produce 15-fluoroerythromycin A and 15-azidoerythromycin A. These new erythromycin analogs provide antibacterial macrolides with unique physicochemical properties and functional groups that allow for selective derivatization.

An array of 15-amido substituted erythromycin A compounds was synthesized using a chemobiosynthesis approach. It was found that while the in vitro antibacterial activities of aryl amides were inferior to erythromycin A, substituted benzylamides showed equivalent and in some cases improved activity against the macrolide-resistant strains. The 15-amidoerythromycins represent a new class of antibacterial macrolides.

Streptomyces rugosporus LL-42D005 was shown to produce the novel pyrroindomycin antibiotics. Production of pyrroindomycin (alpha) and chloro-pyrroindomycin (beta) was characterized in a semi-defined fermentation medium containing glucose, casein, phosphate, vitamins and minerals. Accumulation of pyrroindomycin beta increased with increasing concentrations of glucose, reaching maximum titers at approximately 5g/L glucose. Glucose concentrations greater than 7.5 g/L decreased pyrroindomycin beta yields. Inhibition of pyrroindomycin accumulation at higher glucose concentrations could be reversed by increasing the casein concentration. Ammonium chloride, arginine or glutamine could replace casein as the sole nitrogen source for growth and pyrroindomycin production. Glucose, fructose or mannitol were utilized as the sole carbon source, while sucrose, maltose, glycerol, corn oil and starch were poorly metabolized. Incubation of this isolate in a vitamin-deficient medium resulted in a delay in growth and pyrroindomycin production; this delay was eliminated by the addition of biotin. Addition of L-tryptophan to the medium resulted in the production of pyrroindomycin alpha as the major species.

Two new antibiotics, hongoquercins A and B, were isolated from fermentation extracts of the unidentified fungus LL-23G227. In the optimum medium, titers of the A and B components reached approximately 2.1 g/liter and 0.02 g/liter, respectively. The optimum temperature for antibiotic production was approximately 22 degrees C. Growth was delayed at 15 degrees C but appeared to reach higher levels than was observed at 22 degrees C. Addition of dextrose to growth media increased hongoquercin B production. Hongoquercin A exhibited moderate activity against Gram-positive bacteria. Mechanistic studies conducted in an E. coli imp strain suggested membrane damage as the primary mode of bactericidal action. These compounds also lysed human red blood cells, suggesting a similar mode of action on eukaryotic cells.

The cell wall targeted antifungal activity of Hypoxylon oceanicum LL-15G256 extracts resulted from the production of novel lipodepsipeptides and previously reported macrocyclic polylactones. In an optimized medium, titers of the lipodepsipeptide and the polylactones reached approximately 200-400 mg/liter and 25-50 mg/liter, respectively. The optimum fermentation temperature for production of 15G256 gamma was 28 degrees C. Seawater appeared to have an inhibitory effect on metabolite accumulation at lower fermentation temperatures.

Actinomycete culture LL-D37187 has been found to produce the new polyether antibiotic martinomycin. Taxonomic studies, including morphological, physiological, and cell wall chemistry analyses, revealed that culture LL-D37187 is a novel streptomycete species, and the proposed name is Streptomyces salvialis. Martinomycin exhibits activity against the Southern Army Worm (Spodoptera eridania) and Gram-positive bacteria.

Pyrroindomycins A and B were isolated from fermentations of culture LL-42D005, a strain of Streptomyces rugosporus. Pyrroindomycins possess potent antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci. Their structures have been determined by using 1- and 2-D NMR, mass spectroscopy and chemical degradations. Pyrroindomycins are the first natural products that contain the highly unsaturated pyrroloindole moiety.

The new glycothiohexide antibiotics, which are related to nosiheptide, were identified in fermentations of an actinomycete belonging to the genus "Sebekia". Strain LL-14E605 was classified as a "Sebekia" based on the presence of both mesodiaminopimelic acid and madurose in the cell wall and the presence of pseudosporangia encasing the spores. Culture LL-14E605 was successfully fermented in 10 to 3,000 liters of a complex medium. Antibiotic activity closely followed cell mass accumulation and usually peaked after 4 to 5 days of incubation. Glycothiohexide alpha demonstrated excellent in vitro activity against Gram-positive bacteria with MICs of 0.03 to 0.06 microgram/ml against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. However, glycothiohexide alpha failed to protect mice against a lethal challenge with Staphylococcus aureus Smith unless it was administered prior to challenge.