A new monobactam SQ 28, 332 has been isolated from fermentations of a Flexibacter sp. and the structure 3 was deduced from its spectroscopic properties. SQ 28, 332 exhibits weak antibacterial activity.

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Two new β-lactam antibiotics, namely SQ 28, 502 and SQ 28, 503, have been isolated from fermentations of a Flexibacter sp. They are demethoxy monobactams with oligopeptide side chains and have molecular weights of 1, 462 and 1, 446, respectively. These β-lactams show a high degree of stability to a variety of β-lactamases and act as potent irreversible inactivators of P99 β-lactamase from Enterobacter cloacae. They exhibit weak antibacterial activity.

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A set of chemical and spectroscopic studies using IR and FAB-mass spectral data has been developed to identify monobactams thereby differentiating them from other families of β-lactam antibiotics.

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Pyrrolomycins C, D and E, new members of pyrrolomycins produced by Actinosporangium vitaminophilium SF-2080, have been isolated by chromatography on a basic alumina column. Three antibiotics have chlorinated pyrrole nuclei linked directly or via carbonyl function to the dichlorophenol moiety. Pyrrolomycins C and E are active against Gram-positive bacteria, while the spectrum of pyrrolomycin D is broad including Gram-positive, Gram-negative bacteria and fungi.

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Actinomycete strain OM-173, a new soil isolate, was found to produce five nanaomycin-type antibiotics. Antibiotic OM-173 components αA, αE, αB, βA and βE were isolated from the fermentation broth of strain OM-173 by solvent extraction, silica gel chromatography and preparative thin-layer chromatography. The components are active against mycoplasmas and to a lesser extent against fungi. Strain OM-173 was identified as a strain of genus Streptomyces and differed apparently from Streptomyces rosa var. notoensis, the nanaomycin-producing strain, in cultural characteristics.

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Antibiotic X-14885A is a polyether antibiotic belonging to the class of these natural acid ionophores known as pyrrolethers. The structure of the antibiotic was elucidated by X-ray crystallographic analysis of the hydrated sodium salt, which crystallized as a tetramer containing four antibiotic and water molecules and four atoms of sodium. Antibiotic X-14885A differs from the most well-known member of the class, A-23187, in two respects : the aromatic N-methylamino group present in the latter is replaced by a phenolic hydroxyl, and one of the four aliphatic methyls is replaced by a proton. Antibiotic X-14885A is active against Grampositive bacteria and the spirochete, Treponema hyodysenteriae.

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Safracins, new antibiotics with a novel skeleton, were discovered in a culture broth of Pseudomonas sp. The producing organism has been identified as Pseudomonas fluorescens. Safracins A and B were isolated by ethyl acetate extraction and chromatography on silica gel.

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The chemical structures of safracins A and B are proposed to be 1 and 2 respectively on the basis of their physicochemical properties and spectrometric studies.

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Safracins A and B have antibacterial activity against Gram-positive and Gram-negative bacteria in vitro but no therapeutic activity in mice infected with Staphylococcus aureus. Safracins A and B induce abnormal morphological changes in Echerichia coli cells. Tests with transplantable mice tumors demonstrate that safracins A and B inhibit the growth of P388 leukemia and IMC carcinoma.

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Ancovenin, an inhibitor of angiotensin I converting enzyme isolated from the culture broth of a Streptomyces species, is a dialysable peptide composed of sixteen amino acid residues containing unusual amino acids such as threo-β-methyllanthionine, meso-lanthionine, and dehydroalanine.

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A new antibiotic, dapiramicin, has been isolated from the fermentation broth of Micromonospora sp. SF-1917. Since the dapiramicin exhibited essentially no in vitro activity by usual bioassays, two assay methods for dapiramicin were developed, HPLC and a new bioassay by growth inhibition of fungal mycelia on a slide glass. Fermentation of dapiramicin is also described.

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Antibiotic-resistance genes were shotgun cloned from antibiotic-producing Streptomyces sp. using pock-forming plasmids (pSF689 and pSF765), as cloning vectors. Streptomyces chartreusis SF1623 and S. lividans 66 were used as host strains. The ribostamycin (RSM) resistance gene was cloned from S. ribosidificus SF733 DNA (on a 2.3 Md PstI fragment) into both S. chartreusis SF1623 and S. lividans 66, using pSF689 as vector. Kanamycin (KM), novobiocin (NB), destomycin (DM) and racemomycin (RM) resistance genes were cloned from S. kanamyceticus M1164, S. spheroides M1469, S. rimofaciens M1470 and S. lavendulae A249 genomic DNA into S. lividans 66, using pSF765 as vector. Furthermore two types of KM resistance determinants derived from S. kanamyceticus M1164 were cloned using S. lividans 66, the pSF689 vector. The RSM resistance gene showed no homology to plasmid pSF733 of S. ribosidificus SF733, but hybridized to PstI or BclI digested total DNA of S. ribosidificus SF733.

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¹H and ¹³C NMR spectral studies of lipiarmycin in CDCl₃, and in pyridine-d₅ provided evidence for the six partial structures I-VI and the two sugar units 1 and 2. Acid methanolysis led to the isolation of methyl 2-O-methyl-4-O-homodichloroorsellinate-β-rhamnoside, whose structure was determined by spectroscopic methods.

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Biosynthesis of the ansamycin antibiotic actamycin (2) was markedly increased by the addition of the precursor 3-amino-5-hydroxybenzoic acid (1) to the producing Streptomyces fermentation. Similar addition of the 4-chloro, 6-chloro, N-methyl and O-methyl analogues 4, 6, 5 and 7 of the amino acid 1 reduced actamycin production and did not yield structurally modified ansamycins. These results with the analogues 4, 5 and 7 indicate that the corresponding chlorine, N-methyl and O-methyl substituents present in the nuclei of various ansamycins are introduced at biosynthetic stages beyond the level of the amino acid 1.

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Sensitivity of Pseudomonas aeruginosa to cerulenin was first tested. The result indicated that this bacterium is resistant to cerulenin. Cerulenin-sensitive mutants were isolated from P. aeruginosa PML 1552 by 1-methyl-3-nitro-1-nitrosoguanidine treatment and following carbenicillin plus D-cycloserine screening. Isolated mutants were designated CSM-1 to CSM-19, and some characters of CSM-19, which showed rapid growth almost as well as parent strain in the medium without cerulenin, were examined. The cell growth of CSM-19 was greatly inhibited by 50 μg/ml of cerulenin, but when the mixture of cellular fatty acids or both cis-vaccenic acid and palmitic acid were added to the medium, the growth was partially recovered. Incorporation of radioactivity into fatty acids from [1-¹⁴C]acetate was lowered by cerulenin. Those results mean that the fatty acid synthesis of CSM-19 was decreased by cerulenin. Although cellular fatty acid composition and amount were not notably different between CSM-19 and PML 1552, CSM-19 had less phosphatidylethanolamine, and more phosphatidylglycerol and cardiolipin than PML 1552. CSM-19 was also supersensitive to several other antibiotics, especially to carbenicillin and tetracycline, when compared with PML 1552, although both strains showed identical sensitivity to D-cycloserine, polymyxin B, and chloramphenicol.

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Tetrahydrofuranyl and tetrahydropyranyl derivatives of neospiramycin I at 3 and/or 4' position were synthesized. In vitro and in vivo activities of these derivatives were correlated with the position and configuration of acetal groups. The most effective derivative, 3-a, 4'-a-di-O-tetrahydrofuranylneospiramycin I was comparable to spiramycin I.

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MDL 19, 592 is a new semisynthetic cephalosporin with a good therapeutic potential against Gram-positive bacterial infections when administered orally or parenterally. In the oral treatment of benzylpenicillin-resistant Staphylococcus aureus infections in mice, MDL 19, 592 was superior to cephalexin, cephradine, cefaclor, cefadroxil and cefroxadine. These in vivo results reflect the in vitro superiority expressed by MDL 19, 592 over the other oral cephalosporins against staphylococci. Additionally, MDL 19, 592 orally was superior to cefazolin and cephalothin administered subcutaneously and to a number of penicillinase-resistant penicillins given orally or subcutaneously in the treatment of S. aureus mouse infections. MDL 19, 592 killed S. aureus cells at the same or faster rate than did cephalexin or cephradine. As compared to cephalexin, MDL 19, 592 was marginally superior in vitro against Streptococcus pyogenes and Streptococcus pneumoniae. In vivo, MDL 19, 592 was significantly the more effective of the two against S. pyogenes and marginally more effective against S. pneumoniae. Against Gram-negative organisms, with the exception of Haemophilus influenzae, cephalexin was the more potent of the two antibiotics both in vitro and in vivo. Administered orally to mice, MDL 19, 592 was absorbed as rapidly as cephalexin with both drugs attaining similar concentrations in the blood. MDL 19, 592, like cephalexin, was minimally bound by mouse serum.

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A series of olivanic acid/thienamycin analogues have been prepared by total synthesis. Particular attention was given to the effect of the side-chain substituents on the chemical, β-lactamase and metabolic stability of the final products. All of the compounds possessed a broad and high level of in vitro antibacterial activity against Gram-positive and Gram-negative organisms including β-lactamase-producing strains. Two derivatives (8c) and (8j) were selected for further evaluation on the basis of in vitro activity, ease of synthesis and stability parameters. The improved metabolic stability of the selected analogues, relative to the naturally-occurring olivanic acid, MM 13902, could be demonstrated in terms of better activity, higher blood levels and improved urinary recovery in in vivo studies in mice.

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To resolve discrepancies between its enzymological activity and its in vitro or in vivo activity, 6-acetylmethylenepenicillanic acid (Ro 15-1903), a potent β-lactamase inhibitor, was investigated for its chemical stability and its ability to penetrate the bacterial cell envelope. Although Ro 15-1903 was fairly stable in water or saline, it was found to be unstable in a rich medium, in mouse plasma and in human serum. Decomposition half-lives in Tryptic Soy Broth (TSB) and mouse plasma were determined by spectrometry to be 1.3 hours and 12 minutes respectively. These values were confirmed by a biochemical method for determination of Ro 15-1903. Furthermore, a large enhancement of the in vitro activity was noticed when the assay medium was changed from TSB to a synthetic medium in which Ro 15-1903 was more stable. The ampicillin-potentiating activity marginally increased if a permeability mutant harboring the R6K plasmid, which codes for TEM-1 β-lactmase production, was used instead of the wild-type strain. These results prove that the chemical instability of Ro 15-1903 is the main cause of its disproportionally low activity in vitro and in vivo. Ro 15-1903 is not nonspecifically inactivated by proteins, since it did not lose its activity after incubation with bovine serum albumin (50 mg/ml) for 2 hours at 37°C. It seems to react specifically with β-lactamase.

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The effect of cefmetazole on the growth together with the release of cellular lipoteichoic acid from cefazolin-resistant strains of Staphylococcus aureus was compared with that of cefazolin, cefotiam, cefoxitin and cefuroxime. Bacteriolytic actions were measured by turbidity and bactericidal actions were followed by viable cell count. Release of cellular lipoteichoic acid was measured by the radioactivity in the supernatant of the cultures. Cefmetazole exerted more potent effects on the bacterial growth and induced more marked release of cellular lipoteichoic acid from resistant strains as compared with other β-lactams.

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The inducer activity of seven penicillins for cephalosporinase (CSase) production and their antibacterial activity against CSase-producing strains were studied using clinical isolates of Proteus morganii, P. rettgeri, P. vulgaris, Enterobacter cloacae, and Serratia marcescens. Piperacillin, apalcillin, and methicillin showed rather low inducer activity for CSase production in all strains tested. On the other hand, ampicillin, carbenicillin, and sulbenicillin showed high inducer activity for CSase production. Piperacillin, apalcillin, and ampicillin were less stable to CSases than were carbenicillin, sulbenicillin, and methicillin, but much more stable than benzylpenicillin. In the growing culture of CSase-producing strains, piperacillin and apalcillin were rather stable. Against CSase-producing strains, piperacillin and apalcillin were more active than other penicillins tested.

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