An actinomycete strain No. B-52653 was found to produce an antibiotic selectively active against the in vitro antibiotic resistant mutant of Staphylococcus aureus. Based on taxonomic studies, the name Streptomyces albulus subsp. ochragerus subsp. nov. is proposed for the strain. The microorganism produced two kinds of antibiotics; one identical with gougerotin, the other an amphoteric water soluble dipeptide containing L-alanine. The latter has the molecular formula C₉H₁₅N₃O₆ and is named alahopcin. It has a broad antibacterial spectrum and a synergistic effect with some other antibiotics against some antibiotic resistant staphylococci. Alahopcin has a low toxicity and was effective against experimental infections in mice caused by Staphylococcus aureus.

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A new amino acid, dealanylalahopcin, was isolated from a culture filtrate of Streptomyces albulus subsp. ochragerus; it was also formed by the enzymatic hydrolysis of alahopcin using microbial α-amino acid ester hydrolase. The amino acid was obtained as colorless needles and its molecular formula is C₆H₁₀N₂O₅ It showed very weak antibacterial activity against Gram-positive and Gram-negative bacteria, and weak inhibitory activity against the collagen prolylhydroxylase.

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The structure of alahopcin (nourseimycin) (1), a new dipeptide antibiotic isolated from Streptomyces, has been established to be (2S, 3R)-2-[(L-alanyl)amino]-4-formyl-3-(hydroxyaminocarbonyl) butyric acid. 1 exists in two cyclic hemiacetal type tautomers formed by intramolecular ring closure between the hydroxyamino group and the formyl group in aqueous solution. The structure of the new weakly acidic amino acid (2), a constituent of 1, is revealed to be (2S, 3R)-2-amino-4-formyl-3-(hydroxyaminocarbonyl) butyric acid, and 2 also exists in two cyclic hemiacetal type tautomers in aqueous solution.

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Four new and two known peptide antibiotics containing amiclenomycin (Acm) have been isolated from a culture of Streptomyces venezuelae Tü 2460: L-McIle-L-Acm (1), L-Ile-L-Acm (2), L-MeVal-L-Acm (3), L-MeIle-L-Acm-L-Gln (4), L-Ile-L-Acm-L-Gln (5) and L-Val-L-Acm-L-Gln (6). These di- and tripeptides exhibited antimicrobial activity on a minimal medium against Gram-negative bacteria, which could be reversed by biotin. It was shown that the antibiotics were decomposed by peptidases to provide amiclenomycin (7) after their uptake into cells of Esclterichia coli via peptide-permeases. The antimicrobial activity of the amiclenomycin-peptides was the inhibition of DAPA-aminotransferase by the amiclenomycin-warhead, however, amiclenomycin itself was hardly transported into the cells. Since the amiclenomycin peptides misuse general transport systems, they are presented here as examples for the illicit transport concept.

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Dihydromonacolin L and monacolin X those are structurally related to monacolin K, a potent inhibitor of cholesterol biosynthesis, were isolated from cultures of a mutant of Monascus ruber. The structures of these two metabolites were determined by a combination of physical techniques. Data for dihydromonacolin L and monacolin X as inhibitors of hydroxymethylglutaryl-CoA reductase and sterol biosynthesis in vitro are also given.

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Several fungal strains were found to convert compactin (ML-236B) to 5'-phosphocompactic acid. The product was isolated by solvent extraction and column chromatography, and identified by IR, UV, ¹H NMR, ¹³C NMR and ³¹P NMR spectroscopy. Related structures (monacolin K, L and X) were also transformed to their corresponding phosphorylated analogues. The products were re-converted back to respective parental compounds by treatment with alkaline phosphatase of calf intestine.

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The OA-6129 group of carbapenem antibiotics were phosphorylated with ATP by Brevibacterium ammoniagenes at the primary hydroxyl group of the C-3 pantetheinyl side chain. The phosphorylation resulted in the reduced antimicrobial activity against some Gram-positive bacteria, and the improved activity against some Gram-negative microbes. The increased resistance of the OA-6129 carbapenems due to phosphorylation was significant to mouse renal dehydropeptidase and moderate to the human enzyme. OA-6129A and B₂ phosphates were found to be unsusceptible to A933 acylase, while OA-6129A and B₂ were depantothenylated.

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The production of the antibiotic polypeptide microcin E492 by Klebsiella pneumoniae RYC492 has been studied in respect to the composition of the culture medium. The nature of both the carbon and nitrogen sources had a dramatic effect on the levels of the microcin detected in the supernatants of the liquid cultures. Gluconeogenic precursors such as lactate or citrate led to microcin titers 10 to 100 fold higher than those obtained with glucose. However, neither glycerol nor cAMP stimulated the production, ruling out a typical type of catabolic repression by glucose. Limitation of growth by phosphate or nitrogen led to a marked decrease in production. Treatment with mitomycin C did not result in an enhancement of microcin levels.

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In expectation of improving the antibacterial activity of sulfazecin by chemical modification at the 3- and 4-positions, a number of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(substituted oxyimino)-acetamido]-4-(substituted methyl)-2-azetidinone-1-sulfonic acids were synthesized. Among various 4-substituents explored, the carbamoyloxymethyl group was found to provide a good effect to the antibacterial activity of these 2-azetidinone derivatives. An extensive study of structure-activity relationships led to selecting (3S, 4S)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoacetamido]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, AMA- 1080 (Ro 17-2301), which has highly potent antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, for further biological and subsequent clinical evaluation.

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A series of penicillins and cephalosporins containing the substituted 6-vinyl-1, 2-dihydro-2-oxo- and 1, 4-dihydro-4-oxo-3-pyridinecarboxylic acid side chains has been prepared and compared to piperacillin and cefoperazone. The compounds show good activity when tested in vitro against an array of Gram-negative bacteria. In vitro activity was also demonstrated against several species of Gram-positive bacteria. Two compounds, 14 and 21, show good in vivo activity when tested against Klebsiella pneumoniae, Enterobacter cloacae, and two strains of Pseudomonas aeruginosa.

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(5-Methyl-2-oxo-1, 3-dioxol-4-yl)methyl 7-[D-O-(L-alanyl)mandelamido]-3-[[(5-methyl-1, 3, 4-thiadiazol-2-yl)thio]methyl]-3-cephem-4-carboxylate hydrochloride (KY-109) was synthesized as a bifunctional pro-drug designed to improve the oral absorption of the parent drug (KY-087), a cephalosporin similar in activity to cefamandole. The pro-drug was found to possess the desired factors for an orally active pro-drug, that is, appropriate solubility, lipophilicity and ease hydrolysis into the parent drug. As predicted from these factors, the pro-drug when administered orally to rats was well absorbed, and gave high blood levels of the parent drug.

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From Streptomyces noursei B3, two plasmids-designated pSCY5 and pSCY6-were isolated in addition to the known plasmid pSCY3. Strains carrying one or more of these plasmids generated pocks on a lawn of the plasmid-free strain, S. noursei KL3. The pocks elicited by pSCY3 and pSCY5 belonged to the A type; i.e., showed a clear inhibition zone, while those produced by pSCY6 were of the B type; i.e., exhibited a turbid inhibition zone. The strains carrying either pSCY3 or pSCY5, were also capable of forming pocks on a lawn of S. noursei 6T-11 harboring pSCY6, and vice versa. However, pock formation was not observed between strains harboring pSCY3 and strains carrying pSCY5. The endonuclease cleavage maps of these plasmids revealed that pSCY3 differed clearly from that of pSCY6, whereas pSCY5 was found to be a hybrid plasmid consisting of the entire pSCY3 plasmid and an 8.4Md or longer fragment originating from pSCY6. The pocks elicited by pSCY5 were much smaller than those produced by pSCY3. Transformation experiments showed that pSCY6 elicited pocks in Streptomyces lividans as well as in S. noursei, whereas the pSCY6 transformants of S. lividans failed to produce pocks on a lawn of plasmid-free S. noursei.

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The effects of 7-N-(p-hydroxyphenyl) mitomycin C (M-83), a derivative of mitomycin C, against eight human tumor xenografts serially transplanted into male BALB/c nude mice were evaluated. M-83 showed positive antitumor effect against six out of eight tumor strains. The antitumor spectrum of this agent was similar to that of mitomycin C except for two strains. The serum level of M-83 detected by bioassay was biphasic, elimination half-life T_1/2β was 10.9 minutes and the area under curve AUC⁶⁰₀ was 112.4μg•minute/ml when 15 mg/kg of the agent was administered. In the tumor, the peak concentration and AUC⁶⁰₀ detected by radioassay correlated well with the value of drug efficacy T_RW/C_RW. The ratio of the concentrations detected by bioassay to radioassay in the tumor was approximately 10%, which was thought to be affected by inactivation of the agent in the tumor.

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Bestatin enhanced the antitumor effects of mitomycin C, 5-fluorouracil and cis-dichlorodiammineplatinum against a syngeneic solid tumor of colon adenocarcinoma 26 in BALB/c mice. The enhancement was dependent on administration schedule. Bestatin administration after treatment with the cytotoxic agents was more effective than that made before the treatment.

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Mildiomycin, a new nucleoside antibiotic, selectively inhibits protein synthesis in HeLa cells, and is less active in the inhibition of RNA or DNA synthesis. An increased inhibition of translation by mildiomycin is observed in cultured HeLa cells when they are permeabilized by encephalomyocarditis virus. This observation suggests that this antibiotic does not easily pass through the cell membrane, as occurs with other nucleoside and aminoglycoside antibiotics. The inhibition of translation is also observed in cell-free systems, such as endogenous protein synthesis in a rabbit reticulocyte lysate or the synthesis of polyphenylalanine directed by poly (U). Finally the mode of action of mildiomycin was investigated and the results suggest that the compound blocks the peptidyl-transferase center.

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