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The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.

3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria.

3-Acetyl analogues of thiolactomycin, a thiotetronic acid natural product, were synthesized and profiled against livestock pathogens. Some analogues showed improved activity over thiolactomycin against Staphylococcus aureus and comparable activity against Pasteurella multocida. Several semisynthetically modified analogues of thiolactomycin showed no improvement in activity over thiolactomycin.

Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'-dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were identified as novel antibacterial agents for the treatment of animal disease, especially for livestock respiratory disease. The in vitro microbiological characterization of both CP-101,680 and CP-163,234 was carried out using their parent compounds, viomycin and capreomycin, as controls. This characterization included antibacterial spectrum, influence of media, inoculum size, pH, EDTA, polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition, and time-kill kinetics. Our results indicated that the capreomycin analog, CP-163,234, showed slightly improved in vitro potency over the viomycin analog, CP-101,680. Both analogs showed very potent cell-free protein synthesis inhibition activity and were bactericidal against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP-163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re-growth was observed after 24 hours incubation at both concentrations of CP-101,680.

Cyclopropane carboxylic acid was fed to Saccharopolyspora erythraea NRRL 18643 (6-deoxyerythromycin producer), resulting in the production of 6-deoxy-13-cyclopropyl-erythromycin B. These studies provide further evidence that deoxyerythronolide B synthase has a relaxed specificity for the starter unit.

In a previous report, a plasmid, pIG1, which contained the loading domain from the Streptomyces avermitilis polyketide synthase (PKS), promoters from Streptomyces coelicolor and the DEBS1-TE truncated PKS from Saccharopolyspora erythraea, was integrated into the S. erythraea chromosome, effectively replacing the natural erythromycin loading domain with the avermectin loading domain. In this paper, we report the feeding of short-chained fatty acids to this recombinant strain, and its parent, NRRL 2338. Both strains incorporated exogenously supplied fatty acids to produce novel, biologically active, C-13 substituted erythromycins.

The current study investigated the anticoccidial activity of the ionophore CP-84,657 against laboratory strains of the five major pathogenic species of Eimeria that infect poultry. Based on lesion scores and weight gain, the ionophore CP-84,657 achieved broad-spectrum anticoccidial efficacy in battery trials at doses of 4 and 5 ppm that was equivalent to reference commercial ionophores. In uninfected chickens, 4 ppm of CP-84,657 was the highest dose that gave growth rate and feed efficiency equivalent to commercial agents over 21 days in batteries and 49 days in floor pens. Ionophore CP-84,657 is an efficacious, well-tolerated anticoccidial in chickens, with potency comparable to that of the most potent known ionophores.

The anticoccidial activity of the ionophore CP-82,009 against laboratory isolates of four major species of poultry Eimeria was investigated. Parameters of anticoccidial efficacy that were evaluated were control of lesions and weight suppression. At 4 and 5 ppm, CP-82,009 demonstrated broad-spectrum anticoccidial efficacy in battery trials that was equivalent to reference commercial ionophores. When CP-82,009 was fed to uninfected broiler chickens at efficacious dose levels, growth rate and feed efficiency were found to be equivalent to commercial agents over a 21-day period in batteries and over a 49-day period in floor pens. From the present studies, it appears that CP-82,009 is an efficacious anticoccidial that is well tolerated by chickens, and that it ranks among the most potent anticoccidial ionophores described to date.

A new polyether antibiotic CP-82,009 (C49H84O17) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53676). Following purification by column chromatography and crystallization, the structure of CP-82,009 was elucidated by spectroscopic (NMR and MS) methods. The absolute stereochemistry was determined by a single crystal X-ray analysis of the corresponding rubidium salt. CP-82,009 is among the most potent anticoccidial agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Serpulina (Treponema) hyodysenteriae.

A new polyether antibiotic CP-82,996 (C50H86O16) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53764). Following purification by silica gel column chromatography and crystallization, the structure of CP-82,996 was determined by a single crystal X-ray analysis. The structure is closely related to monensin, but is unique in that it contains two sugar groups, whereas monensin has none. The 1H and 13C NMR chemical shifts and assignments for CP-82,996 were elucidated, and they were compared with those determined previously for monensin. CP-82,996 is active against certain Gram-positive bacteria, and is a very potent anticoccidial agent. It effectively controlled chicken coccidiosis caused by several Eimeria species at 5-10 ppm in feed, and is 10-20 times more potent than monensin.

A new polyether antibiotic CP-84,657 (C45H78O14) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53708). Following purification by column chromatography and crystallization, the structure of CP-84,657 was elucidated by spectroscopic (NMR and MS) methods. The absolute stereochemistry was determined by a single crystal X-ray analysis of the corresponding rubidium salt. CP-84,657 is among the most potent anticoccidal agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Treponema hyodysenteriae.

A Free-Wilson analysis of the antibacterial activity found in a variety of quinoxaline 1,4-dioxides prepared and tested in these laboratories unexpectedly predicted that potent activity should be found in the case where the heterocyclic ring system was substituted with an acetyl group in the 2 position and a hydroxymethyl group in the 3 position (2). The synthesis and antibacterial activity of this compound, which was actually isolated in the hemiketal form (3), and of several of its derivatives are reported. 1-Hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide (3) possesses exceptional activity in vivo against Escherichia coli, Salmonella choleraesuis, and Pasteurella multocida.

Some 3-[(alkylthio)methyl]quinoxaline 1-oxide derivatives (1) have been synthesized and screened for antibacterial activity. 2-Acetyl-3-[(methylsulfonyl)methyl]quinoxaline 1-oxide (7a) was found to possess good in vitro activity against some pathogens important to veterinary medicine including Treponema hyodysenteriae, a causative agent in swine dysentery. In an in vivo experiment, this compound (7a) completely protected pigs against a swine dysentery challenge over a 21-day period.

The synthesis, separation, and structure determination of 6- and 7-acetyl--3-methyl-2-quinoxalinecarboxamide 1,4-dioxides are reported together with a comparison of their antibacterial activity. The structural assignment of these 6- and7-acetyl isomers was based on NMR analysis of related mono-N-oxide derivatives, which were obtained by treatment of the quinoxaline 1,4-dioxides with acetic anhydride--acetic acid or trimethyl phosphite. The compounds were screened for in vitro and in vivo activity against Escherichia coli, Salmonella choleraesuis, Pasteurella multocida, and Streptococcus pyogenes. Although the isomers were found to possess similar activity, the 7-acetyl isomer was more active therapeutically in mice than the 6-acetyl isomer when administered parenterally.

A new monocarboxylic acid ionophore antibiotic related to zincophorin, CP-78,545 (1), was found in the culture broth of Streptomyces sp. N731-45. CP-78,545 was extracted with organic solvents and purified by column chromatography. The metabolite, which is active in vitro against certain Gram-positive bacteria, as well as the anaerobe Treponema hyodysenteriae, and a coccidium Eimeria tenella, was isolated as a water insoluble magnesium salt (2) in 2:1 (ligand/metal) stoichiometry. The structure of CP-78,545 was elucidated by spectroscopic (NMR and MS) methods, and the relative stereochemistry was determined by single-crystal X-ray analysis of the cadmium salt (3). CP-78,545, i.e., 24-dehydrozincophorin, is unique since its molecular backbone contains a terminal double bond previously not found in other polyether ionophores.