Isolation of an aminoglycoside hypersensitive mutant and its application in screening.

An aminoglycoside hypersensitive mutant, Kp-126, was isolated from the aminoglycoside-resistant strain, Kp-8, of Klebsiella pneumoniae through selection using sorbistin, a non-aminocyclitol-aminoglycoside antibiotic. The mutant Kp-126 was approximately 100-fold more sensitive to sorbistin than the parent strain Kp-8. The mutant also showed hypersensitivity to various aminocyclitol-aminoglycoside antibiotics. K. pneumoniae Kp-126 was used in screening and a new aminoglycoside antibiotic, 3,3'-neotrehalosadiamine (BMY-28251), was discovered in the fermentation broths of soil isolate strain of Bacillus pumilus.

Sorbistin, a new aminoglycoside antibiotic complex of bacterial origin. I. Production, isolation and properties.

A strain of a new Pseudomonas species produced the aminoglycoside antibiotic complex, sorbistin, which was separated by ion-exchange chromatography into three bio-active components A1, A2 and B, and two bio-inactive components C and D. Sorbistins A1, A2 and B showed moderate intrinsic activity against a wide range of bacterial species and inhibited most of the aminoglycoside-resistant organisms. Sorbistin A1 exhibited the highest activity among the three bio-active components. Sorbistins showed low order of acute toxicity in mice.

New cirramycin-family antibiotics F-1 and F-2. Selection of producer mutants, fermentation, isolation, structural elucidation and antibacterial activity.

Two new 16-membered macrolides, cirramycins F-1 and F-2, were isolated from the culture filtrate of a mutant strain B-1425 of Streptomyces cirratus JTB-3. The antibiotics were also produced by bio-transformation of cirramycin A1 using a blocked mutant strain A-0033. Structures of F-1 and F-2 have been elucidated by spectral interpretation and analysis of acid degradation products. Both involved isomeric modification of a neutral sugar; F-1 contained L-rhodinose, and F-2 L-amicetose. Based on spectral data, cirramycin F-1 and antibiotic A6888C were found to be identical. Cirramycins F-1 and F-2 are active against Gram-positive bacteria, but less active than cirramycin A1.

Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. I. Production, isolation, chemical properties and biological activities.

Five unidentified actinomycete strains produced a series of novel antiviral antibiotics which have a unique 2,6-dialkyl-10-ethyl-3(or 9)-hydroxy-13-tridecanelactam nucleus substituted with 3-amino-3,6-dideoxy-L-talose or 3-amino-3,6-dideoxy-L-mannose(L-mycosamine). The antibiotic components exhibited potent inhibitory activity against influenza virus type A Victoria strain infection in Madin Darby canine kidney cells by the cytopathic effect reduction assay.

Dynemicins, new antibiotics with the 1,5-diyn-3-ene and anthraquinone subunit. I. Production, isolation and physico-chemical properties.

Dynemicin A, a novel antibiotic containing the bicyclo[7.3.1]-1,5-diyn-3-ene and 1,4,6-trihydroxyanthraquinone functionalities, was isolated from the culture broth of Micromonospora chersina sp. nov. M956-1. The antibiotic exhibited potent in vitro antibacterial and cytotoxic activity, and in in vivo, it cured mice from lethal Staphylococcus aureus infection and prolonged survival time of mice inoculated with murine tumors. Three satellite components, dynemicins L, M and N, were also isolated from the culture broth and chemically characterized.

Cispentacin, a new antifungal antibiotic. I. Production, isolation, physico-chemical properties and structure.

A new antibiotic, cispentacin, was isolated from the culture broth of a Bacillus cereus strain, L450-B2. The antibiotic is water-soluble and amphoteric; its structure was determined by spectroscopic analysis and chemical synthesis to be (1R,2S)-2-aminocyclopentane-1-carboxylic acid. Cispentacin demonstrated only weak in vitro activity against certain fungi but strong protection of mice from lethal infection of Candida albicans A9540.

Antibacterial activity of BMY-28142, a novel broad-spectrum cephalosporin.

BMY-28142, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- (1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate, exhibited a well-balanced, extended-spectrum of antibacterial activity both in vitro and in vivo. Against Staphylococci and Streptococci, BMY-28142 was about four to ten times more active than ceftazidime and comparable to cefotaxime. Most Enterobacteriaceae were more susceptible to BMY-28142 than to ceftazidime, though strains of Pseudomonas aeruginosa were slightly more sensitive to ceftazidime. BMY-28142 showed potent activity against Gram-negative bacteria resistant to ceftazidime and/or cefotaxime. Bactericidal activity of BMY-28142 against 10 strains of P. aeruginosa was superior to that of ceftazidime. In bacterial infection models in mice, BMY-28142 was more effective than ceftazidime against three Gram-positive and three Gram-negative pathogens. The anti-pseudomonal in vivo activity of BMY-28142 was nearly comparable to that of ceftazidime. The blood levels and urinary excretion rates of BMY-28142 in mice were similar to those of ceftazidime.

Elsamicins, new antitumor antibiotics related to chartreusin. I. Production, isolation, characterization and antitumor activity.

New antitumor antibiotics, elsamicins A and B, were isolated from the culture broth of an unidentified actinomycete strain J907-21 (ATCC 39417). They are structurally related to chartreusin, containing the common aglycone, chartarin, but contain different sugar moieties. Elsamicin A, the major component, has an amino sugar in the molecule which makes the antibiotic much more water-soluble than chartreusin. Elsamicin A exhibits strong inhibitory activity against various murine tumors including leukemia P388, leukemia L1210, and melanoma B16 but elsamicin B which lacks the amino sugar showed only marginal activity. The potency of elsamicin A was 10-30 times more potent than that of chartreusin in terms of minimum effective dose.

Boholmycin, a new aminoglycoside antibiotic. I. Production, isolation and properties.

A novel aminoglycoside antibiotic, boholmycin, was produced by Streptomyces hygroscopicus H617-25 isolated from a soil sample collected in Bohol Island, the Philippines. It has a pseudotetrasaccharide structure composed of a heptose, two aminosugars and dicarbamoyl-scyllo-inositol. Intrinsic antibacterial activity of boholmycin is weak but it exhibits broad spectrum activity against Gram-positive and Gram-negative bacteria including aminoglycoside-resistant strains. Boholmycin is non-toxic in mice at 1,000 mg/kg intravenously.

Quartromicin, a complex of novel antiviral antibiotics. I. Production, isolation, physico-chemical properties and antiviral activity.

A strain of Amycolatopsis orientalis No. Q427-8 (ATCC 53884) was found to produce a complex of new antiviral antibiotics, quartromicin which consisted of at least six components A1, A2, A3, D1, D2 and D3. Structural studies suggested that they are a novel type of molecules unrelated to any known antibiotics. Each component of quartromicin exhibited antiviral activity against herpes simplex virus type 1, influenza virus type A and human immunodeficiency virus.

Glidobactins A, B and C, new antitumor antibiotics. I. Production, isolation, chemical properties and biological activity.

New antitumor antibiotic glidobactins A, B and C were isolated from the cultured broth of a gliding bacterium, Polyangium brachysporum sp. nov. No. K481-B101. They are novel molecules carrying the common cyclic tripeptide nucleus substituted with different alpha, beta, gamma, delta-unsaturated fatty acids. Glidobactins exhibit broad inhibitory activity against fungi and yeasts, and prolong the life span of mice inoculated with P388 leukemia cells.

Enzymatic formation of glidobactamine: a peptide nucleus of glidobactins A, B and C, new lipopeptide antitumor antibiotics.

Glidobactin deacylating activity was found in a bacterial strain of Pseudomonas sp. Glidobactamine, a key intermediate for acyl analogues of glidobactin, was isolated from the enzymatic degradation products of glidobactins after treatment using a column of fibrous active gel on which the cells of the Pseudomonas strain were immobilized. The chemical structure of glidobactamine was confirmed as the intact peptide moiety of glidobactins by chemical reformation of glidobactin A from glidobactamine and 2,4-dodecadienoic acid which is the constitutive fatty acid of glidobactin A.

Enhanced production of the minor components of glidobactins in Polyangium brachysporum.

Polyangium brachysporum sp. nov. strain ATCC 53080 produces a novel type of antifungal and antitumor antibiotic complex, glidobactins A, B and C. Enhanced production of minor components, glidobactins B and C, was achieved by medium modification. The addition of soybean oil or corn oil, which are rich in unsaturated C18 fatty acids, to the fermentation medium led to an increased production of components B and C. Productivity of component C was selectively enhanced by the addition of oleic acid-rich oils, olive oil and Tween 80 (polyoxyethylene sorbitan mono-oleate). Furthermore, precursing palmitoleate, linoleate and oleate permitted the direct biosynthesis of components A, B and C, respectively. The fermentation with 3% addition of an appropriate oil at initial time provided an optimal production of component B or C.

Porothramycin, a new antibiotic of the anthramycin group: production, isolation, structure and biological activity.

A new antitumor antibiotic porothramycin was produced by a new strain of Streptomyces albus. The antibiotic was isolated in two active forms, the natural free hydroxyl form (porothramycin A) or the crystalline methyl ether form (porothramycin B) depending upon the isolation process used. Structural studies established that porothramycin is a new member of the pyrrolo[1,4]benzodiazepine group antibiotics having only one substituent on the benzene ring. The antibiotic exhibited antimicrobial activity against Gram-positive bacteria and anaerobes and significantly prolonged the survival times of mice implanted with experimental tumors.

In vitro and in vivo evaluations of BMY-28100, a new oral cephalosporin.

A new semisynthetic oral cephalosporin, BMY-28100, was evaluated for in vitro and in vivo antibacterial activities in comparison with cefaclor and cephalexin. BMY-28100 showed in vitro activity 3- and 10-fold more potent than that of cefaclor against Staphylococcus aureus and Streptococcus pneumoniae, respectively. BMY-28100 was slightly better than cefaclor and about 4 times more active than cephalexin against Haemophilus influenzae and Neisseria gonorrhoeae. Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis were comparably susceptible to BMY-28100 and cefaclor. The bactericidal activity of BMY-28100 against S. aureus, E. coli and P. mirabilis was equal to or twice as high as MIC value, which was similar to that of cefaclor. The stability of BMY-28100 against penicillinases was nearly comparable to that of cefaclor, whereas cefaclor was somewhat unstable to cephalosporinases. BMY-28100 was about twice as active as cefaclor against three Gram-positive bacterial infections. BMY-28100 was also more potent against infections of H. influenzae and P. mirabilis, but slightly less active against E. coli Juhl than cefaclor. Blood level parameters of BMY-28100 were significantly superior to those of cefaclor and slightly better than cephalexin in mice and rats. The urinary recovery of BMY-28100 was somewhat higher and comparable to that of cefaclor and cephalexin, respectively. BMY-28100 was more stable than cefaclor in human and calf sera at 37 degrees C.

Bu-2470, a new peptide antibiotic complex. I. Production, isolation and properties of Bu-2470 A, B1 and B2.

A strain of Bacillus circulans produced a complex of basic peptide antibiotics designated Bu-2470, which was found to contain four active components, A, B1, B2a and B2b. Bu-2470 A specifically inhibited various Pseudomonas species including P. aeruginosa, P. maltophilia and P. putida, but otherwise its antibacterial spectrum was limited to certain Gram-negative organisms. Bu-2470 B1 and B2 (B2a + B2b) showed broad antibiotic activity against Gram-positive and Gram-negative bacteria including Pseudomonas species. The physicochemical and biological properties of Bu-2470 B1 and B2 are very similar to those of the octapeptin group of antibiotics.

Bu-2470, a new peptide antibiotic complex. II. Structure determination of Bu-2470 A, B1, B2a and B2b.

The structures of Bu-2470 A, B1, B2a, and B2b have been determined. Bu-2470 A is a simple octapeptide having no fatty acid moiety, while Bu-2470 B1, B2a and B2b are octapeptides that have been acylated with a beta-hydroxy C11 or C10 fatty acid. The octapeptide structure of Bu-2470 components was found identical with that of octapeptin C1, hence generic names of octapeptin C0, C2, C3 and C4 are proposed for Bu-2470 A, B1, B2a and B2b, respectively.

Glysperin, a new antibiotic complex of bacterial origin. I. Production, isolation and properties.

Strains of Bacillus cereus produced a complex of new antibiotics, glysperins A, B and C. They are basic, water-soluble antibiotics and active against Gram-positive and Gram-negative bacteria including aminoglycoside-resistant organisms. Glysperin A is a major component of the antibiotic complex and approximately two to four times more active than components B and C.

Tallysomycin, a new antitumor antibiotic complex related to bleomycin. V. Production, characterization and antitumor activity of tallysomycin S10b, a new biosynthetic tallysomycin derivative.

Tallysomycin S10b is a biosynthetic derivative of tallysomycin B obtained by precursor amine-feeding fermentation. Tallysomycin S10b contains 1,4-diaminobutane as the terminal amine moiety in place of spermidine of tallysomycin B, and its assigned structure was verified by carbon-13 NMR spectrum. The antitumor activity of tallysomycin S10b was comparable to that of tallysomycin A against sarcoma 180 but less active than the latter against leukemia P388. Tallysomycin S10b was less toxic than tallysomycin A in terms of acute and subacute LD50 values. The nephrotoxic potential of tallysomycin S10b in rats was less than that of tallysomycin A.

New antifungal antibiotics, pradimicins D and E. Glycine analogs of pradimicins A and C.

New antifungal antibiotics pradimicins D and E were isolated from the culture filtrates of Actinomadura hibisca P157-2 (ATCC 53557) and its mutant A2660 (ATCC 53762). The structure of pradimicin D is N-[[(5S,6S)-5-O-[4,6-dideoxy-4-(methylamino)-3-O-(beta-D- xylopyranosyl)-beta-D-galactopyranosyl]-5,6,8,13-tetrahydro-1,6,9,14- tetrahydroxy-11-methoxy-3-methyl-8,13-dioxobenzo[a]naphthacen++ +-2-yl] carbonyl]glycine, based on spectral analyses compared to pradimicin A. Pradimicin E is the des-N-methyl analog of pradimicin D. Pradimicins D and E were equal in activity to pradimicin A in vitro against a variety of fungi and in vivo against Candida albicans A9540 in mice.