X-14766A is a novel, chlorine containing polyether antibiotic produced by Streptomyces inalachitofuscus subsp. downeyi. The antibiotic is active in vitro gainst Gram-positive bacteria and is capable of complexing and transporting monovalent as well as divalent metal cations.
This report describes the isolation and chemical characterization of antibiotic X-14766A, the first halogen containing polyether antibiotic, from fermented cultures of Streptomyces malachitofuscus subsp. downeyi. The structure of this novel antibiotic was determined by X-ray analyses of the thallium and rubidium salts. In addition to the chlorine atom, which is attached to a salicylic acid chromophore, the molecule contains a tricyclic di-spiroketal ring system and an ethyl ester group.
Structures of antitumor antibiotics BBM-928 A, B and C have been determined. They are cyclic decadepsipeptides containing 3-hydroxy-6-methoxyquinaldic acid as a chromophore. Two amino acids, not found in nature, L-β-hydroxy-N-methylvaline and trans-(3S, 4S)-4-hydroxy-2, 3, 4, 5-tetrahydropyridazine-3-carboxylic acid, were identified as structural constituents of the antibiotic. In gross structure, BBM-928 resembles the echinomycin group of antibiotics which are cyclic octadepsipeptides having a quinoxaline chromophore, but BBM-928 differs from the latter group by virtue of the lack of a sulfur-containing cross linkage.
In an effort to improve the antibacterial activity of 7β-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporins by introducing a methoxyimino group into the 7-acyl side chain, geometrically isomeric 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acids and their derivatives were selectively synthesized. Structurally related acid derivatives were also synthesized. A facile and practical synthesis of an important starting material, 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid, for the preparation of SCE-1365 which is now under extensive clinical trial was achieved.
In order to improve the antibacterial activity of 7β-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporins new derivatives having a methoxyimino moiety in the 7-acyl side chain and related compounds were synthesized. Of these, 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido] cephalosporins were found to possess excellent activity against a variety of Gram-positive and Gram-negative bacteria including β-lactamase-producing strains. An extensive study of structure-activity relationships led to the selection of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylic acid, SCE-1365, for further biological and clinical evaluation.
Alternative syntheses of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-cephalosporins ( 1) were investigated. Of these, a sequence of reactions starting from 6avia8a, 9a, 13a and 13b afforded a convenient route to 1a which is especially useful for the preparation of labeled cefmenoxime. Structures of nitrone compounds which were formed as by-products are discussed.
Selective 6'-N-alkylation of 1, 2'-di-N-benzyloxycarbonylfortimicin B was effected by both catalytic and chemical reductive alkylation in the presence of aldehydes. These facile selective 6'-N-alkylations were used as the basis of the preparations of the 6', 6'-di-N-methylfortimicins A and B, and the 6'-N-methylfortimicins A and B. Of these new 6'-N-methylated fortimicins, only 6'-N-methylfortimicin A has appreciable antibacterial activity, which was about half that of fortimicin A.
The stability of cefonicid (SK&F 75073) towards representatives of six major classes of β-lactamases was determined using a spectrophotometric assay. Cefonicid was stable to hydrolysis by the Type I enzyme from Enterobacter cloacae and by the enzyme from the anaerobe, Bacteroides fragilis. It was 6 to 7 times more stable than cefamandole to the Type IIIA and B enzymes from Escherichia coli, a little less stable than this antibiotic to the Type V enzyme from E. coli, and of equal stability to the Type IV enzyme from Klebsiella aerogenes. Cefonicid was a non-competitive inhibitor (Ki of 0.8×10-6 M) of cephalothin hydrolysis by the Type I enzyme.
Biochemical activities of new carbapenem antibiotics, C-19393 H2(H2) and C-19393 S2(S2), were examined in comparison with those of mecillinam using Escherichia coli. H2 showed remarkably high affinity for penicillin-binding protein (PBP) 2, and high affinity for PBPs 1 and 3. S2 showed high affinity for PBP 2, moderate affinity for PBP 1 and low affinity for PBP 3. They induced ovoid cells at lower concentrations and cell lysis at higher concentrations. The inhibitory potency of H2 for peptidoglycan synthesis was similar to that of mecillinam at lower concentrations up to 0.1μg/ml. At concentrations higher than 0.1 μg/ml, the inhibition rate by H2 gradually increased up to 100%, whereas that by mecillinam remained at 60% level. The MICs of H2, S2 and mecillinam corresponded to the lowest concentrations giving 60% of inhibition of peptidoglycan synthesis at which concentrations the function of PBP 2 seemed to be prevented completely. These findings indicate that the primary targets of H2 and S2 are PBP 2 involved in cell shape determination in E. coli.
New carbapenem antibiotics, C-19393 S2 and H2, have been found to be potent and broad-spectrum inhibitors of β-lactamases. Among 11 types of β-lactamases tested, those from Escherichia coli (plasmid-bearing), Klebsiella pneumoniae, Proteus vulgaris, Serratia marcescens and Bacteroides fragilis were especially sensitive. They also inhibited cephalosporinases insensitive to clavulanic acid. The inhibition by C-19393 S2 and H2 was of progressive type, except for the inhibition of E. coli enzyme (plasmid-mediated type I) by C-19393 H2. The inhibition of E. coli β-lactamase by C-19393 S2 was irreversible, while that by C-19393 H2 was reversible.
Lonomycin A at various concentrations was tested for its inhibitory effect on Toxoplasma multiplication in host cells cultured in vitro. Results indicated that lonomycin A at a concentration of 0.01μg per ml in TC-199 medium demonstrated a high degree of antitoxoplasma activity with complete inhibition of Toxoplasma multiplication in the host cells. Lymphokines, a supernatant produced from spleen cells of mice infected chronically with Toxoplasma gondii, inhibited Taxoplasma multiplication in mice macrophage and kidney cell monolayers. However, lonomycin A inhibited completely Toxoplasma multiplication in non-specific cells, i.e. not only in mice macrophages and kidney cells but also in cells of human and other animal species.
Clinical isolates of Streptococcus faecalis were found to contain streptomycin (SM)-phosphotransferase, kanamycin (KM)-acetyltransferase and KM-adenylyltransferase. The existence of a new type of KM-phosphotransferase was suggested from aminoglycoside substrate profiles.
The MICs of cefotiam and cefazolin against K. pneunzoniae DT-S were Unaffected by the inoculum size and were 0.1 and 1.56μg/ml, respectively. Bactericidal and bacteriolytic activities of the cephalosporins were more potent in bacterial concentrations of 107 colonyforming units (CFU)/ml than in concentrations of 108 CFU/ml. Both activities of cefotiam were more markedly influenced by bacterial concentrations than those of cefazolin. Therapeutic activity of cefotiam was about 9-15 times as potent as that of cefazolin in experimental pneumonia caused by K. pneumoniae DT-S in mice, and this finding was in accordance with the ratio of in vitro antibacterial activities of the two cephalosporins as judged by the MICs or the bactericidal and bacteriolytic activities in bacterial suspension of 107 CFU/ml. The range of concentrations of cefotiam which induced cell filamentation in vitro, was wider than that of cefazolin. This difference, however, was not reflected on the therapeutic activities of the two cephalosporins in the model infection. In the pneumonic lungs, definite therapeutic doses of both cephalosporins (80 mg of cefotiam per kg and 640 mg of cefazolin per kg) produced mainly bacteriolysis of the challenge organisms.