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Novel bacterial topoisomerase inhibitors (NBTIs) are the newest members of gyrase inhibitor broad-spectrum antibacterial agents, represented by the most advanced member, gepotidacin, a 4-amino-piperidine linked NBTI, which is undergoing phase III clinical trials for treatment of urinary tract infections (UTI). We have extensively reported studies on oxabicyclooctane linked NBTIs, including AM-8722. The present study summarizes structure activity relationship (SAR) of AM-8722 leading to identification of 7-fluoro-1-cyanomethyl-1,5-naphthyridin-2-one based NBTI (16, AM-8888) with improved potency and spectrum (MIC values of 0.016-4 μg/mL), with Pseudomonas aeruginosa being the least sensitive strain (MIC 4 μg/mL)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: The authors were gainfully employed either at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ 07033, USA or Kyorin Pharmaceutical, Tokyo and declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In this study, we aimed to create synthetic polymer receptors with the fluorescence signalling ability, using molecular imprinting, precisely designed template molecules, and site-specific post-imprinting modifications, which can mimic conjugated proteins and are capable of specific molecular recognition, and wherein successful binding can be indicated by a change in fluorescence. A molecularly imprinted APO-type nanocavity with a reconstructable domain was prepared by co-polymerisation of a template molecule containing cephalexin conjugated to polymerisable groups via a Schiff base, a disulphide bond, and a cross-linker, followed by hydrolysis of the Schiff base and a disulphide exchange reaction. Fluorescence-based indication of binding was devised by the Schiff base formation reaction with 4-formylsalicylic acid, and the interacting site was introduced via a disulphide exchange reaction with 4-mercaptobenzoic acid, yielding a multifunctional mature (HOLO)-type molecularly imprinted nanocavity. The ability to indicate binding events using changes in the fluorescence of the HOLO polymer was investigated, and it was revealed that the target antibiotic cephalexin can be selectively detected in aqueous media with high affinity ( K a = 1.1 × 10 4 M -1 ). Furthermore, the proposed sensor exhibited the potential to detect spiked cephalexin in chicken extracts with a limit of detection of 18 μM (1.3 ppm). The proposed fluorescence-sensing system based on molecular imprinting and post-imprinting modification is expected to enable the development of advanced materials for the specific detection of trace antibiotics in complex samples.

The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC 90 values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16-40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Phase III study demonstrated that vonoprazan-based Helicobacter pylori eradication therapy achieved higher eradication rate compared with lansoprazole. However, there is no study that evaluated the efficacy of vonoprazan in a large sample in real world. We investigated the eradication rate and safety of vonoprazan-based eradication therapy compared with our randomized control trial using second-generation proton pump inhibitor (PPIs)., Methods: (First study) A total of 147 patients who have H. pylori infection were randomly assigned to receive either, esomeprazole (EPZ) group and rabeprazole (RPZ) group. (Second study) 1,688 patients who have H. pylori infection underwent primary eradication with triple therapy involving vonoprazan. In both studies, triple therapy with amoxicillin, clarithromycin, and PPI or vonoprazan was performed, and eradication effect was assessed by an urea breath test., Results: (First study) Eradication rate was 77.5% in the EPZ group and 68.4% in the RPZ group; no significant difference was observed between the 2 groups. (Second study) The successful primary eradication rate was 90.8%. There was no severe adverse effect., Conclusions: The eradication rate of vonoprazan-based triple therapy was remarkably higher compared with second-generation PPIs-based triple therapy in real world. Vonoprazan is very likely to become the first option for future eradication therapy., (© 2018 S. Karger AG, Basel.)

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Biological agents inhibiting TNF-α and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease., Case Presentation: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year., Conclusion: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.

Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. (R)-Hydroxy-1,5-naphthyridinone left-hand side (LHS) oxabicyclooctane linked pyridoxazinone right-hand side (RHS) containing NBTIs showed a potent Gram-positive antibacterial profile. SAR around the RHS moiety, including substitutions around pyridooxazinone, pyridodioxane, and phenyl propenoids has been described. A fluoro substituted pyridoxazinone showed an MIC against Staphylococcus aureus of 0.5 μg/mL with reduced functional hERG activity (IC50 333 μM) and good in vivo efficacy [ED90 12 mg/kg, intravenous (iv) and 15 mg/kg, oral (p.o.)]. A pyridodioxane-containing NBTI showed a S. aureus MIC of 0.5 μg/mL, significantly improved hERG IC50 764 μM and strong efficacy of 11 mg/kg (iv) and 5 mg/kg (p.o.). A phenyl propenoid series of compounds showed potent antibacterial activity, but also showed potent hERG binding activity. Many of the compounds in the hydroxy-tricyclic series showed strong activity against Acinetobacter baumannii, but reduced activity against Escherichia coli and Pseudomonas aeruginosa. Bicyclic heterocycles appeared to be the best RHS moiety for the hydroxy-tricyclic oxabicyclooctane linked NBTIs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Conjugated-protein mimics were obtained using a new molecular imprinting strategy combined with post-imprinting modifications. An antibiotic was employed as a model template molecule, and a polymerizable template molecule was designed, which was composed of the antibiotic and two different prosthetic groups attached through a disulfide bond and Schiff base formation. After co-polymerization with a cross-linker, the template molecule was removed together with the prosthetic groups, yielding the apo-type scaffold. Through conjugation of the two different prosthetic groups at pre-determined positions within the apo-type scaffold, the apo cavity was transformed into a functionalized holo cavity, which enables the on/off switching of the molecular recognition ability, signal transduction activity for binding events, and photoresponsive activity., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Procalcitonin-guided antibiotic therapy for community-acquired pneumonia is effective and safe. However, the usefulness of procalcitonin for aspiration pneumonia and its nutrition-related outcomes are unknown., Methods: We conducted a noninferiority randomized controlled study in patients with aspiration pneumonia who were admitted to our hospital between September 2010 and January 2012. We randomly assigned 105 patients to groups with different durations of antibiotic therapy based on the procalcitonin levels upon admission (procalcitonin group) or according to the standard guidelines (control group). The primary endpoints were relapse of aspiration pneumonia and death within 30 days, with a predefined noninferiority boundary of 10%. Secondary endpoints included duration of antibiotic exposure. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined continuation of oral nutritional intake, relapse of pneumonia, and in-hospital death., Results: The rate of relapse and death within 30 days were similar in the procalcitonin and control groups (25% versus 37.5%; difference, -12.5%; 95% confidence interval, -30.9% to 5.9%). Procalcitonin-guided antibiotic therapy significantly shortened the median duration of antibiotic exposure (5 versus 8 days; p<0.0001); however, the continuation of oral intake was not increased (56% versus 50%; p=0.54). A multivariable analysis showed a significant association between the continuation of oral nutritional intake and the body mass index upon admission., Conclusions: Procalcitonin-guided antibiotic therapy for aspiration pneumonia can shorten the duration of antibiotic exposure, but it does not increase the continuation of oral intake (UMIN000004800)., (© 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The emergence of drug-resistant microorganisms is an important medical and social problem. Drug-resistant microorganisms are thought to grow selectively in the presence of antibiotics. Most clinically isolated drug-resistant microorganisms have mutations in the target genes for the drugs. While any of the many mutagens in the environment may cause such genetic mutations, no reports have yet described whether these mutagens can confer drug resistance to clinically important microorganisms. We investigated how environmental mutagens might be implicated in acquired resistance to antibiotics in clinically important microorganisms, which causes human diseases. We selected mutagens found in the environment, in cigarette smoke, or in drugs, and then exposed Pseudomonas aeruginosa to them. After exposure, the incidence of rifampicin- and ciprofloxacin-resistant P. aeruginosa strains markedly increased, and we found mutations in genes for the antibiotic-target molecule. These mutations were similar to those found in drug-resistant microorganisms isolated from clinical samples. Our findings show that environmental mutagens, and an anticancer drug, are capable of inducing drug-resistant P. aeruginosa similar to strains found in clinical settings., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Hepatic organic anion transporters OATP1B1 and OATP1B3 are expressed at the sinusoidal membrane of hepatocytes and contribute to the hepatic uptake of a wide variety of clinically used drugs. To identify the antibiotics that interact with the human organic anion transporters OATP1B1 and OATP1B3, we applied a screening system using fluorescent probes. Twenty-six antibiotics with a variety of mechanisms of action were examined. The screening demonstrated that four antibiotics inhibited OATP1B1-mediated transport and 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner. Antibiotics that inhibited OATP1B3-mediated transport tended to exhibit higher affinity than those that inhibited OATP1B1-mediated transport. To clarify whether the antibiotics that interacted with OATP1B1 and/or OATP1B3 were substrates for these transporters, an uptake study was performed. Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of ceftriaxone, cefmetazole, cefoperazone, and cefotaxime. Macrolides were not significantly transported by either transporter. In conclusion, the results demonstrated that our system is a useful method for the rapid screening of transporter-antibiotic interaction, and we found novel substrates. Our results indicate that OATP1B1 and/or OATP1B3 contribute to the transport process of some antibiotics, and that drug-drug interactions associated with these transporters could occur after the administration of antibiotics.

ICM0201 (1), a new inhibitor of murine osteoclastogenesis in culture was isolated from a fermentation broth of Cunninghamella sp. F-1490. The structure of ICM0201 was determined to be (3S,10aR)-3,4a-dihydroxy-2,3,4,4a-tetrahydro-2H-pyrano[3,2-b]benzo[e]morpholine-9-carboxylic acid by spectroscopic analyses and chemical studies. The structure of 1 is unique in that the tricycle ring system is composed of aminal and hemiacetal bonds.

In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.78 microg/ml and showed weak cytotoxicity against bone marrow cells.

Some derivatives of bactobolin were prepared from bactobolin (1) by transformation of the dichloromethyl group at C-3 to the hydroxymethyl, carboxylic acid, methanesulfonyloxymethyl and aldehydeoxime groups. The derivatives proved to be less active than the parent antibiotic 1 against bacteria as well as cytotoxicity, indicating that the functionality at C-3 considerably influences the biological activity.

Peptide antibiotics tripropeptins A, B, C, D and Z were isolated from cultured cells and broth of Lysobacter sp. The differences among these components are in the lengths of the alkyl side chain. Tripropeptins are active against Gram-positive bacteria including MRSA in vitro. Bactericidal activity of tripropeptin C disappeared in the simultaneous presence of chloramphenicol, a bacteriostatic agent.

We have isolated four related compounds named phepropeptins A, B, C, and D, as inhibitors of proteasome proposed to regulate many cellular functions. From an NMR analysis, the phepropeptins appeared as cyclic hexapeptides, differing in the two residues of the constituent amino acids from one another, with four conserved amino acid moieties. Based on an amino acid analysis, we synthesized two possible cyclic peptides to phepropeptin B that differ in the configurations. A comparison of the properties between the natural and synthesized compounds revealed that the structure of phepropeptin B was cyclo(-L-Leu-D-Phe-L-Pro-L-Phe-D-Leu-L-Val-). The phepropeptins showed inhibition to the proteasomal chymotrypsin-like activity but not to alpha-chymotrypsin.

A novel 16-membered lactone antibiotic named tubelactomicin A was isolated from the culture broth of Nocaradia sp. MK703-102F1. The structure of tubelactomicin A was assigned by spectroscopic analysis and the absolute configuration was determined by X-ray crystallographic analysis.

A novel 16-membered lactone antibiotic named tubelactomicin A was isolated from the culture broth of an actinomycete strain. The producing organism, designated MK703-102F1, was identified as a member of Nocardia. Tubelactomicin A was isolated from the culture broth by Diaion HP20 absorption, ethyl acetate extraction, silica gel and Sephadex LH-20 column chromatographies and centrifugal liquid-liquid partition chromatography (CPC). Tubelactomicin A showed strong activity against acid-fast bacteria including the drug-resistant strains.

A new depsipeptide antibiotic, vinylamycin, was isolated from the culture broth of an actinomycete strain. The producing organism, designated MI982-63F1, was identified as a member of Streptomyces. Vinylamycin was isolated from the culture broth by extraction with EtOAc and purified by crystallization from EtOAc. The structure of vinylamycin was determined by spectroscopic analysis and degradation studies. Vinylamycin showed antimicrobial activities against Gram-positive bacteria including MRSA.

New antibiotics designated decatromicins A and B were isolated from the culture broth of Actinomadura sp. MK73-NF4. They were purified by butyl acetate extraction, silica gel column chromatography, silica gel TLC and Sephadex LH-20 column chromatography. Decatromicins A and B inhibited growth of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA).

The structures of decatromicins A and B that strongly inhibit the growth of MRSA were elucidated by the analysis of various NMR experiments. The planar structure was determined by 1H, 13C, COSY, HMQC and HMBC NMR spectra. The relative configuration of aglycone was elucidated by NOESY experiments and the absolute structure was determined by application of the modified Mosher's method. The absolute structure of glycosyl moiety was determined by X-ray analysis of the O-(p-bromobenzoyl) derivative.

The absolute structure of a new antibiotic lactonamycin is described. The NMR studies deduced one of four possible structures for the aglycon attached by a rhodinose through glycosidic bond. The stereochemistry of the sugar obtained by an acid hydrolysis was determined to be L-form by measuring optical rotation. The stereochemistry of the aglycon was determined by X-ray crystallographic analysis.

Lactonamycin (1) was isolated from a culture broth of Streptomyces rishiriensis MJ773-88K4. Antibiotic 1 exhibited antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

Antibacterial antibiotics, diperamycin (1) was produced in the culture broth of Streptomyces griseoaurantiacus MK393-AF2. Various spectroscopic analyses of 1 suggested that 1 belonged to a member of cyclic hexadepsipeptide antibiotic. Antibiotic 1 had potent inhibitory activity against various Gram-positive bacteria including Enterococcus seriolicida and methicillin-resistant Staphylococcus aureus.

Strain MJ347-81F4 has been found to produce two new cyclic thiazolyl peptide antibiotics, components A and B. Taxonomic studies including morphological and physiological characteristics and chemical analysis of whole cells of the producing strain revealed this microorganism to belong to genus Amycolatopsis, and so we designated the strain Amycolatopsis sp. MJ347-81F4. After 10 to 12 days of fermentation, most of the antibacterial activity was present mainly in the mycelial cake and reached its maximum level. In comparison with reference compounds, A as the major component showed excellent in vitro activity against gram-positive bacteria including highly methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis with MICs in the range of concentration of 0.006 to to approximately 0.1 microg/ml. The results on the antimicrobial activity against thiazolyl peptide-resistant mutants of Bacillus subtilis NRRL B-558 indicated that the possible molecular target of MJ347-81F4 component A might be the 50S subunits of the ribosome, the inactivation of which would inhibit protein synthesis.

3-epi-Actinobolin was synthesized by the chemical transformation of actinobolin involving a key step of the reconstruction of fused delta-lacton skeleton via intramolecular acylation reaction. The analogue with low toxicity weakly inhibits Gram-positive and Gram-negative bacteria.

A novel 19-membered macrocyclic lactam antibiotic, cremimycin, was isolated from the culture broth of an actinomycete strain. The producing organism, designated MJ635-86F5, was identified as a member of Streptomyces. Cremimycin was isolated from the mycelial cake by extraction with CHCl3-MeOH and precipitation with hexane-MeOH. The structure of cremimycin was determined by spectroscopic study. Cremimycin showed broad antimicrobial activities against Gram-positive bacteria including MRSA.

Some derivatives of bactobolin were prepared from bactobolin (1) by radical reduction and formation of the fused azetidine ring. The derivatives proved less active than the parent antibiotic 1 against bacteria, indicating that dichloromethyl group at C-3 position play an important role in biological activity.

A new antibiotic designated polyketomycin was isolated from the culture broth of Streptomyces sp. MK277-AF1. It was purified by ethyl acetate extraction, Sephadex LH-20 column chromatography and centrifugal partition chromatography (CPC). It inhibited growth of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Its MICs were less than 0.2 microgram/ml. Polyketomycin exhibited cytotoxic activity against nine tumor cell lines at concentrations of 0.9-5.2 micrograms/ml.

A new antibiotic, polyketomycin, was isolated from the culture broth of Streptomyces sp. MK277-AF1. The structure was determined by various NMR spectroscopies, X-ray crystallographic analysis and degradation experiments.

Formamicin, an antifungal antibiotic, was isolated from the cultured broth of an actinomycete strain. The strain was isolated from a soil collected at Setagaya-ku, Tokyo, Japan, and identified as Saccharothrix sp. MK27-91F2. Formamicin was extracted with acetone from cultured mycelia and purified by silicagel and Sephadex LH-20 column chromatographies and CPC (Centrifugal liquid-liquid Partition Chromatography). Formamicin showed strong antimicrobial activity against phytopathogenic fungi.

A novel antifungal antibiotic, formamicin, was isolated from the culture broth of Saccharothrix sp. MK27-91F2. The absolute structure of formamicin was determinated by spectroscopic and X-ray crystallographic analysis and degradation study.

The structures of epoxyquinomicins A (1), B (2), C (3) and D (4) were determined by spectroscopic studies. Compound 1 was determined to be (5R,6S)-2-(3-chloro-2-hydroxybenzoylamino)-5-hydroxymethyl-5,6-epo xy- 2-cyclohexene-1,4-dione. Compound 2 was revealed to be the dechlorinated derivative of 1. Compounds 3 and 4 were determined to be the reduced derivative of 2 and 1, respectively.

A new structural class of the antibiotic, epoxyquinomicins A, B, C and D were isolated from the culture broth of the strain MK299-95F4, which was related to Amycolatopsis sulphurea. Antimicrobial activity of epoxyquinomicins A and B were weak against Gram-positive bacteria, and epoxyquinomicins C and D showed almost no antimicrobial activity and no cytotoxicity. All these antibiotics showed improvement of collagen induced arthritis in vivo.

The structure of heliquinomycin which was isolated from the culture broth of Streptomyces sp. MJ929-SF2 was studied by NMR spectroscopies, X-ray crystallographic analysis and degradation experiments. Heliquinomycin is the first member of glycosylated rubromycins and griseorhodins group antibiotics.

The absolute configurations of pyralomicin la and pyralomicin 2a were determined by X-ray crystallographic analyses of crystalline 7'-O-p-bromobenzoylpyralomicin 1a and 2'-O-p-bromobenzoylpyralomicin 2a derived from pyralomicin 1a and pyralomicin 2a using anomalous scattering of the bromine atom. The absolute configurations of pyralomicins 1b approximately 1d and 2b approximately 2e were suggested to be the same as pyralomicin 1a and pyralomicin 2a, respectively, by comparing the circular dichroism spectra.

Benanomicin A showed a broad antifungal spectrum, inhibiting the growth of all test strains of 41 yeasts, 23 dimorphic fungi, 23 dematiaceous fungi, 16 aspergilli, and 19 dermatophytes, with the exception of 12 zygomycetic strains. The MIC values of benanomicin A were comparable to those of amphotericin B against Cryptococcus. Rhodotorula, Trichosporon, Geotrichum, Sporothrix, and some dermatophytes, but were two to eightfold higher than those of amphotericin B against other fungal pathogens tested. The action of benanomicin A was fungicidal.

The biosynthesis of pyralomicin 1a (1) was studied by feeding of 13C and 15N labeled compounds to the culture of Microtetraspora spiralis MI178-34F18. The result indicated that the benzopyranopyrrole unit of 1 was derived from two units of acetate, one unit of propionate and one unit of proline, and that the cyclitol unit of 1 was derived from glucose metabolites. And 4'-O-CH3 was derived from the S-CH3 group of methionine.

Novel antibiotics, pyralomicins 1a approximately 1d, 2a approximately 2c were isolated from the culture broth of Microtetraspora spiralis MI178-34F18. The structures of pyralomicins were determined by various NMR spectral analyses including 1H-15N HMBC and 13C¿1H¿ NOE difference experiments.

New ansamycins designated hydroxymycotrienins A and B were isolated from culture broths of Bacillus sp. BMJ958-62F4. The two antibiotics inhibited more strongly the growth of human cervical cancer cell lines of human papilloma virus (HPV) positive than that of HPV negative cell lines. The structures, some biological and biochemical properties are reported.

The derivatives of tetrodecamycin (1), being introduced acyl, carbamoyl and alkyl groups at 14-hydroxyl group and modified at exo-methylene group, were synthesized and evaluated on their antibacterial activities. Although 14-O-substituted tetrodecamycins (3 approximately 19) showed weak activity against Pasteurella piscicida, they were more active against Gram-positive bacteria than 1. Among them, 15 showed approximately 10-fold higher activity than 1. The derivatives (20 approximately 23) modified at 4 or 5 positions had moderate antibacterial activity. The absolute structure of 4(R),5-dibromotetrodecamycin (23) was determined by X-ray crystallographic analysis.