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  • Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-15
    Hideki Hashizume, Kiyoko Iijima, Kazuma Yamashita, Tomoyuki Kimura, Shun-ichi Wada, Ryuichi Sawa, Masayuki Igarashi

    Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by <i>Amycolatopsis</i> sp. ML1-hF4, Published online: 15 November 2017; doi:10.1038/ja.2017.135

    更新日期:2017-11-15
  • Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168-141F8
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-15
    Ryuichi Sawa, Yumiko Kubota, Maya Umekita, Masaki Hatano, Chigusa Hayashi, Masayuki Igarashi

    Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168-141F8Quadoctomycin, a 48-membered macrolide antibiotic from <i>Streptomyces</i> sp. MM168-141F8, Published online: 15 November 2017; doi:10.1038/ja.2017.140

    更新日期:2017-11-15
  • Synthesis and antibacterial activity of novel lincomycin derivatives. IV. Optimization of an N-6 substituent
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-08
    Ko Kumura, Yoshinari Wakiyama, Kazutaka Ueda, Eijiro Umemura, Yoko Hirai, Keiko Yamada, Keiichi Ajito

    The design and synthesis of lincomycin derivatives modified at the C-6 and C-7 positions are described. A substituent at the C-7 position is a 5-aryl-1,3,4-thiadiazol-2-yl-thio group that generates antibacterial activities against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes carrying an erm gene. An additional modification at the C-6 position was explored in application of information regarding pirlimycin and other related compounds. These dual modifications were accomplished by using methyl α-thiolincosaminide as a starting material. As a result of these dual modifications, the antibacterial activities were improved compared with those of compounds with a single modification at the C-7 position. The antibacterial activities of selected compounds in this report against macrolide-resistant S. pneumoniae and S. pyogenes with an erm gene were superior to those of telithromycin.

    更新日期:2017-11-08
  • Incentivising innovation in antibiotic drug discovery and development: progress, challenges and next steps
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Victoria L Simpkin, Matthew J Renwick, Ruth Kelly, Elias Mossialos

    Political momentum and funding for combatting antimicrobial resistance (AMR) continues to build. Numerous major international and national initiatives aimed at financially incentivising the research and development (R&D) of antibiotics have been implemented. However, it remains unclear how to effectively strengthen the current set of incentive programmes to further accelerate antibiotic innovation. Based on a literature review and expert input, this study first identifies and assesses the major international, European Union, US and UK antibiotic R&D funding programmes. These programmes are then evaluated across market and public health criteria necessary for comprehensively improving the antibiotic market. The current set of incentive programmes are an important initial step to improving the economic feasibility of antibiotic development. However, there appears to be a lack of global coordination across all initiatives, which risks duplicating efforts, leaving funding gaps in the value chain and overlooking important AMR goals. This study finds that incentive programmes are overly committed to early-stage push funding of basic science and preclinical research, while there is limited late-stage push funding of clinical development. Moreover, there are almost no pull incentives to facilitate transition of antibiotic products from early clinical phases to commercialisation, focus developer concentration on the highest priority antibiotics and attract large pharmaceutical companies to invest in the market. Finally, it seems that antibiotic sustainability and patient access requirements are poorly integrated into the array of incentive mechanisms.

    更新日期:2017-11-01
  • Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Yoshinari Wakiyama, Ko Kumura, Eijiro Umemura, Satomi Masaki, Kazutaka Ueda, Yasuo Sato, Yoko Hirai, Yoshio Hayashi, Keiichi Ajito

    In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4′-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4′-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.

    更新日期:2017-11-01
  • New antituberculous drugs derived from natural products: current perspectives and issues in antituberculous drug development
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Masayuki Igarashi, Yoshimasa Ishizaki, Yoshiaki Takahashi

    Tuberculosis is one of the most common and challenging infectious diseases worldwide. Especially, the lack of effective chemotherapeutic drugs for tuberculosis/human immunodeficiency virus co-infection and prevalence of multidrug-resistant and extensively drug-resistant tuberculosis remain to be serious clinical problems. Development of new drugs is a potential solution to fight tuberculosis. In this decade, the development status of new antituberculous drugs has been greatly advanced by the leading role of international organizations such as the Global Alliance for Tuberculosis Drug Development, Stop Tuberculosis Partnership and Global Health Innovative Technology Fund. In this review, we introduce the development status of new drugs for tuberculosis, focusing on those derived from natural products.

    更新日期:2017-11-01
  • Self-control of the PHO regulon: the PhoP-dependent protein PhoU controls negatively expression of genes of PHO regulon in Streptomyces coelicolor
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Seomara Martín-Martín, Antonio Rodríguez-García, Fernando Santos-Beneit, Etelvina Franco-Domínguez, Alberto Sola-Landa, Juan Francisco Martín

    Phosphate control of the biosynthesis of secondary metabolites in Streptomyces is mediated by the two component system PhoR–PhoP. Linked to the phoR–phoP cluster, and expressed in the opposite orientation, is a phoU-like encoding gene with low identity to the phoU gene of Escherichia coli. Expression of this phoU-like gene is strictly dependent on PhoP activation. We have isolated a PhoU-null mutant and used transcriptomic and RNA-sequencing (RNA-seq) procedures to identify its transcription start site and regulation. RNA-seq studies identified two transcription start sites, one upstream of phoU and the second upstream of the mptA gene. Whereas transcription of PhoU is entirely dependent on PhoP, expression of the downstream mtpA gene is only partially dependent on PhoP activation. The phoU mutant grows more slowly than the parental strain, sporulates poorly and the spores lack pigmentation. Production of actinorhodin and undecylprodigiosin decreased in the phoU mutant, indicating that PhoU has a positive modulating effect on production of these antibiotics. Indeed, transcriptional studies of expression of the actII-ORF4 and redD genes indicated that the PhoU protein activates expression of these antibiotic regulators. Using the glpQ1 promoter as in vivo reporter of the activity of the PHO regulon genes, we observed that expression of glpQ1 is negatively modulated by PhoU. These results were confirmed by reverse transcription-PCR studies of three genes of the PHO regulon; that is, glpQ1, pstS and phoR. In conclusion, PhoU acts as a negative modulator of expression of the PHO regulon genes and as phoU expression is strictly dependent on PhoP activation, this mechanism appears to work as a feed-back control mechanism (self-regulation).

    更新日期:2017-11-01
  • Selective catalytic hydrogenation of the N-acyl and uridyl double bonds in the tunicamycin family of protein N-glycosylation inhibitors
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Neil PJ Price, Michael A Jackson, Karl E Vermillion, Judith A Blackburn, Jiakun Li, Biao Yu

    Tunicamycin is a Streptomyces-derived inhibitor of eukaryotic protein N-glycosylation and bacterial cell wall biosynthesis, and is a potent and general toxin by these biological mechanisms. The antibacterial activity is dependent in part upon a π-π stacking interaction between the tunicamycin uridyl group and a specific Phe residue within MraY, a tunicamycin-binding protein in bacteria. We have previously shown that reducing the tunicamycin uridyl group to 5,6-dihydrouridyl (DHU) significantly lowers its eukaryotic toxicity, potentially by disrupting the π-stacking with the active site Phe. The present report compares the catalytic hydrogenation of tunicamycin and uridine with various precious metal catalysts, and describe optimum conditions for the selective production of N-acyl reduced tunicamycin or for tunicamycins reduced in both the N-acyl and uridyl double bonds. At room temperature, Pd-based catalysts are selective for the N-acyl reduction, whereas Rh-based catalysts favor the double reduction to provide access to fully reduced tunicamycin. The reduced DHU is highly base-sensitive, leading to amide ring opening under mild alkaline conditions.

    更新日期:2017-11-01
  • Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Hayamitsu Adachi, Koichi Nakae, Shuichi Sakamoto, Chisato Nosaka, Sonoko Atsumi, Masabumi Shibuya, Nobuaki Higashi, Motowo Nakajima, Tatsuro Irimura, Yoshio Nishimura

    Microbial metabolites have attracted increasing interest as a source of therapeutics and as probes for biological mechanisms. New microbial metabolites and derivatives targeted at inflammation and bone disease therapy have been identified by focusing on prostaglandin release, osteoblast differentiation and immune cell functions. These modulators of inflammatory processes and bone disease contribute to our understanding of biological mechanisms and support identification of the therapeutic potential of drug lead candidates. The present review describes recent advances in the chemistry and analysis of inhibitors of prostaglandin release or other functional molecules of immune cells, as well as inducers of osteoblast differentiation, including biological and pharmacological activities.

    更新日期:2017-11-01
  • Cellular uptake of modified aminoglycosides
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Kaivin Hadidi, Ezequiel Wexselblatt, Jeffrey D Esko, Yitzhak Tor

    The uptake of modified amino- and guanidino-glycosides derived from kanamycin, tobramycin and neomycin in native and mutant CHO cells is examined using confocal microscopy and flow cytometry, illustrating the significance of multivalency for mammalian cell internalization of carriers that specifically interact with cell surface heparan sulfate proteoglycans.

    更新日期:2017-11-01
  • Our microbes not only produce antibiotics, they also overproduce amino acids
    J. Antibiot. (IF 2.237) Pub Date : 2017-11-01
    Sergio Sanchez, Romina Rodríguez-Sanoja, Allison Ramos, Arnold L Demain

    Fermentative production of amino acids is an important goal of modern biotechnology. Through fermentation, micro-organisms growing on inexpensive carbon and nitrogen sources can produce a wide array of valuable products including amino acids. The amino acid market is $8 billion and mainly impacts the food, pharmaceutical and cosmetics industries. In terms of tons of amino acids produced per year by fermentation, L-glutamate is the most important amino acid produced (3.3 million), followed by L-lysine (2.2 million). The bacteria producing these amino acids are among the top fermentation organisms with respect to titers. Corynebacterium glutamicum is the best producer.

    更新日期:2017-11-01
  • New eremophilane and dichlororesorcinol derivatives produced by endophytes isolated from Ficus ampelas
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Yoshihito Shiono, Niken Istikhari Muslihah, Takuma Suzuki, Nanang Rudianto Ariefta, Chairil Anwar, Handojo Hadi Nurjanto, Takako Aboshi, Tetsuya Murayama, Keitaro Tawaraya, Takuya Koseki, Jun Yoshida, Narandulam Usukhbayar, Shota Uesugi, Ken-ichi Kimura

    The novel compound, 11-O-methylpetasitol (1), was isolated from Penicillium sp. N-175-1, and two new compounds, cosmochlorins D (5) and E (6), were isolated from Phomopsis sp. N-125. In addition, three known eremophilane sesquiterpenes, sporogen-AO1 (2), petasol (3) and 6-dehydropetasol (4), were isolated from Penicillium sp. N-175-1. The structures of 1, 5 and 6 were elucidated by a combination of extensive spectroscopic analyses, including 2D NMR, high-resolution electrospray ionization time-of-flight mass spectrometry (HRESITOFMS) and chemical reactions. Compounds 2, 3, 5 and 6 exhibited cytotoxicity to HL60 and 2 and 3 to HeLa cells. Furthermore, 2 and 3 showed robust growth-restoring activity of a Saccharomyces cerevisiae (cdc2-1 rad9Δ) mutant strain, whereas 5 and 6 exhibited minor growth-restoring activity in this strain. Thus, these compounds may inhibit the growth of HL60 and HeLa cells by blocking the cell cycle, and they may be utilized as new lead compounds that act as inhibitors of survival signal transduction pathways.

    更新日期:2017-10-30
  • Enantiospecific total synthesis of the squalene synthase inhibitors (–)-CJ-13,982 and its enantiomer from a common intermediate
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Dayna Sturgess, Zongjia Chen, Jonathan M White, Mark A Rizzacasa

    The total syntheses of both the natural and unnatural enantiomers of the alkyl citrate natural product CJ-13,982 (1) from the common d-ribose-derived acid 6 are described.

    更新日期:2017-10-30
  • A new eremophilane sesquiterpene from the fungus Xylaria sp. V-27 and inhibition activity against degranulation in RBL-2H3 cells
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Abdou Tchoukoua, Takuma Suzuki, Nanang Rudianto Ariefta, Takuya Koseki, Yusuke Okawa, Ken-ichi Kimura, Yoshihito Shiono

    A new eremophilane sesquiterpene, 13,13-dimethoxyintegric acid (1), together with known compound integric acid (2) have been isolated from a fungus, Xylaria sp. V-27, obtained from a dead branch. The structure of 1 was established by means of spectroscopic analyses. 1 and 2 promoted growth restoring activity against the mutant yeast strain (Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ)) and inhibited degranulation of rat basophilic leukemia RBL-2H3 cells stimulated by immnunoglobulin G + 2,4-dinitrophenylated-bovine serum albumin (IgE+DNP-BSA), thapsigargin and A23187.

    更新日期:2017-10-30
  • Destination of aminoglycoside antibiotics in the ‘post-antibiotic era’
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Yoshiaki Takahashi, Masayuki Igarashi

    Aminoglycoside antibiotics (AGAs) were developed at the dawn of the antibiotics era and have significantly aided in the treatment of infectious diseases. Aminoglycosides have become one of the four major types of antibiotics in use today and, fortunately, still have an important role in the clinical treatment of severe bacterial infections. In this review, the current usage, modes of action and side effects of AGAs, along with the most common bacterial resistance mechanisms, are outlined. Finally, the recent development situation and possibility of new AGAs in the ‘post-antibiotic era’ are considered.

    更新日期:2017-10-30
  • Phenazine carboxylic acid and its derivative induce osteoblast differentiation in preosteoblastic MC3T3-E1 cells but adipocyte differentiation in pluripotent mesenchymal C3H10T1/2 cells
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Shuichi Sakamoto, Takumi Watanabe, Yasuko Kohda, Masatomi Iijima, Ryuichi Sawa, Maiko Okada, Hayamitsu Adachi, Yoshio Nishimura, Manabu Kawada

    Osteoblast and adipocyte are differentiated from mesenchymal stem cells and dysregulation of the differentiation might result in disease, such as osteoporosis and diabetes. To find small compounds that induce osteoblast differentiation, we screened an in-house natural compounds library with mouse preosteoblastic MC3T3-E1 cells using alkaline phosphatase (ALP) expression as an early osteoblast marker. We found that phenazine-1-carboxylic acid (PCA), one of the major phenazine derivatives produced by Pseudomonas, induced osteoblast differentiation in the cells at micromolar concentrations. PCA acted synergistically with an agonist of hedgehog signaling in inducing ALP activity in the cells. We also found that 2-hydroxy-PCA (2H-PCA) induced osteoblast differentiation in the cells but 2-methoxy-PCA and 1-hydroxy-phenazine did not. Unexpectedly, treatment of mouse pluripotent mesenchymal C3H10T1/2 cells with PCA or 2H-PCA induced an obvious morphological change. Oil Red O staining and real-time reverse-transcription PCR analysis revealed that PCA induced not osteoblast differentiation but adipocyte differentiation in C3H10T1/2 cells. These compounds could allow us to investigate the mechanism of osteoblast and adipocyte differentiation in the two model cell systems through a chemical biology approach.

    更新日期:2017-10-30
  • Challenges and discoveries in the total synthesis of complex polyketide natural products
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Ian Paterson, Nelson Yuen Sum Lam

    Structurally complex polyketide natural products, isolated from a variety of marine and terrestrial sources, continue to provide a valuable source of rewarding targets for the synthetic chemist to tackle. In this account, we provide an overview of the total synthesis of several structurally fascinating polyketides with promising anticancer activity completed in our group based on our versatile asymmetric aldol methodology—spirastrellolide A methyl ester, leiodermatolide, rhizopodin and chivosazole F—and highlight the unanticipated challenges and discoveries encountered.

    更新日期:2017-10-30
  • Lanostane triterpenoids from fruiting bodies of basidiomycete Stereum sp., structures and biological activities
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Jian-Neng Yao, Lin Chen, Yang Tang, He-Ping Chen, Zhen-Zhu Zhao, Zheng-Hui Li, Tao Feng, Ji-Kai Liu

    Twelve new lanostane triterpenoids, sterenoids A–L (1–12) have been isolated from fruiting bodies of the basidiomycete Stereum sp. Compounds 1–12 are rare 14(13→12)abeo-lanostane triterpenoids featuring remarkable 13R configurations that discriminate from the previously covered counterparts. Their structures and absolute configurations are assigned on the basis of in-depth one- and two-dimensional NMR spectroscopic analysis, as well as unbiased quantum chemical NMR and electronic CD calculations. All isolates are evaluated for their in vitro cytotoxicity against five human tumor cell lines. Compound 5 exhibits potent cytotoxic activities against tumor cell lines HL-60 and SMMC-7721 with IC50 values of 4.7 and 7.6 μM, respectively.

    更新日期:2017-10-30
  • Amycolatopsins A–C: antimycobacterial glycosylated polyketide macrolides from the Australian soil Amycolatopsis sp. MST-108494
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-25
    Zeinab G Khalil, Angela A Salim, Daniel Vuong, Andrew Crombie, Ernest Lacey, Antje Blumenthal, Robert J Capon

    A southern Australian soil isolate, Amycolatopsis sp. MST-108494, was subjected to a panel of fermentation and media optimization trials, supported by analytical chemical profiling, to detect and enhance production of a rare class of secondary metabolites. Chemical fractionation of two complementary fermentations yielded three new polyketides, identified by detailed spectroscopic analysis as the glycosylated macrolactones, amycolatopsins A (1), B (2) and C (3), closely related to the ammocidins and apoptolidins. Amycolatopsins 1 and 3 selectively inhibited growth of Mycobacterium bovis (BCG) and Mycobacterium tuberculosis (H37Rv) when compared with other Gram-positive or Gram-negative bacteria, with 3 exhibiting low levels of cytotoxicity toward mammalian cells. Thus, our data reveal promising structure activity relationship correlations where the antimycobacterial properties of amycolatopsins are enhanced by hydroxylation of the 6-Me (that is, 1 and 3), whereas mammalian cytotoxicity is decreased by hydrolysis of the disaccharide moiety (that is, 3).

    更新日期:2017-10-30
  • Current landscape and future prospects of antiviral drugs derived from microbial products
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-11
    Naoki Takizawa, Manabu Yamasaki

    Viral infections are a major global health threat. Over the last 50 years, significant efforts have been devoted to the development of antiviral drugs and great success has been achieved for some viruses. However, other virus infections, such as epidemic influenza, still spread globally and new threats continue to arise from emerging and re-emerging viruses and drug-resistant viruses. In this review, the contributions of microbial products isolated in Institute of Microbial Chemistry for antiviral research are summarized. In addition, the current state of development of antiviral drugs that target influenza virus and hepatitis B virus, and the future prospects for antivirals from natural products are described and discussed.

    更新日期:2017-10-11
  • Large-scale preparation of key building blocks for the manufacture of fully synthetic macrolide antibiotics
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-11
    Philip C Hogan, Chi-Li Chen, Kristen M Mulvihill, Jonathan F Lawrence, Eric Moorhead, Jens Rickmeier, Andrew G Myers

    Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.

    更新日期:2017-10-11
  • Anthraquinones from the saline-alkali plant endophytic fungus Eurotium rubrum
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-11
    Yonggang Zhang, Airong Jia, Huabin Chen, Menghua Wang, Gang Ding, Liyan Sun, Li Li, Meixue Dai

    Saline-alkali plant endophytes similar as marine mangrove plant-derived ones are a big member of microbes inhabiting in tissues of plants without causing obvious disease to their hosts, and they must adapt to the extreme environment of high osmolarity and nutrient deprivation in plant, which are different from terrestrial plant endophytes. Owing to the unique bio-environments, endophytes originated from mangrove plants are being considered as a new resource of natural product research and diverse secondary metabolites with a wide range of bioactivities have been isolated. Compared with those of marine mangrove plant-derived endophytes, chemical investigation of saline-alkali plant-derived endophytic fungi have just begun, and only several natural products were isolated from these unique environmental fungi.Suaeda salsa L.

    更新日期:2017-10-11
  • Ascosteroside D, a new mitochondrial respiration inhibitor discovered by pesticidal screening using insect ADP/ATP carrier protein-expressing Saccharomyces cerevisiae
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-11
    Yoshihiro Watanabe, Yukihiro Asami, Satomi Narusawa, Shohei Hashimoto, Masato Iwatsuki, Kenichi Nonaka, Yasuo Shinohara, Takahiro Shiotsuki, Naoya Ichimaru, Hideto Miyoshi, Satoshi Ōmura, Kazuro Shiomi

    A new lanostane-type triterpenoid, ascosteroside D, was isolated from a fungus, Aspergillus sp. FKI-6682. It inhibited insect ADP/ATP carrier protein (AAC)-expressing Saccharomyces cerevisiae in glycerol-containing medium, but did not inhibit Δaac S. cerevisiae in glucose-containing medium. It is hypothesized that ascosteroside D inhibits ATP production in mitochondria.

    更新日期:2017-10-11
  • Biological activity of intervenolin analogs with a phenyl substituent
    J. Antibiot. (IF 2.237) Pub Date : 2017-10-11
    Hikaru Abe, Manabu Kawada, Masayuki Igarashi, Shun-ichi Ohba, Chigusa Hayashi, Chiharu Sakashita, Takumi Watanabe, Masakatsu Shibasaki

    Intervenolin analogs with a phenyl substituent at the 2- or 3-position were synthesized. The compounds (3–11) showed weak or no inhibitory activity toward the growth of MKN-74 gastric adenocarcinoma cells, even in the presence or absence of the corresponding Hs738 stromal cells, whereas 2-substituted analogs exhibited selective anti-Helicobacter pylori activity. Introduction of a pendant side chain on the nitrogen alleviated their acute toxicity in mice. The 2-phenyl-substituted analogs are reasonable structural templates for structure–activity relationship studies toward the development of anti-H. pylori agents that do not affect human cells.

    更新日期:2017-10-11
  • Bisoxazolomycin A: a new natural product from ‘Streptomyces subflavus subsp. irumaensis’ AM-3603
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Wilaiwan Koomsiri, Yuki Inahashi, Tōru Kimura, Kazuro Shiomi, Yōko Takahashi, Satoshi Ōmura, Arinthip Thamchaipenet, Takuji Nakashima

    Bisoxazolomycin (1), oxazolomycin A2 (2) and oxazolomycin A (3) were identified by physicochemical screening approach from a culture broth of ‘Streptomyces subflavus subsp. irumaensis’ AM-3603. Compound 2 is a hydrolyzed analog of 3 at the β-lactone ring, and 1 is a new dimeric analog of 2. Compounds 1 and 2 exhibited less potent antibacterial activity and cytotoxicity than 3, which might be due to lack of the β-lactone ring.

    更新日期:2017-10-11
  • Pteridic acids C–G spirocyclic polyketides from the marine-derived Streptomyces sp. SCSGAA 0027
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Xu-Hua Nong, Xiao-Yi Wei, Shu-Hua Qi

    Five new pteridic acids C–G (1–5) were isolated from a culture broth of the marine-derived actinomycete Streptomyces sp. SCSGAA 0027. Their complete structures were elucidated on the basis of NMR data, modified Mosher’s method and quantum chemical calculations. Furthermore, their cytotoxicity, antiviral and antimicrobial activities were also evaluated.

    更新日期:2017-10-11
  • Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Junichi Taira, Koji Morita, Shotaro Kawashima, Tomohiro Umei, Hiroki Baba, Taira Maruoka, Hideyuki Komatsu, Hiroshi Sakamoto, James C Sacchettini, Shunsuke Aoki

    The enzymes responsible for biotin biosynthesis in mycobacteria have been considered as potential drug targets owing to the important role in infection and cell survival that the biotin synthetic pathway plays in Mycobacterium tuberculosis. Among the enzymes that comprise mycobacterium biotin biosynthesis systems, 7,8-diaminopelargonic acid synthase (DAPAS) plays an essential role during the stationary phase in bacterial growth. In this study, compounds that inhibit mycobacterial DAPAS were screened in the virtual chemical library using an in silico structure-based drug screening (SBDS) technique, and the antimycobacterial activity of the selected compounds was validated experimentally. The DOCK–GOLD programs utilized by in silico SBDS facilitated the identification of a compound, referred to as KMD6, with potent inhibitory effects on the growth of model mycobacteria (M. smegmatis). The subsequent compound search, which was based on the structural features of KMD6, resulted in identification of three additional active compounds, designated as KMDs3, KMDs9 and KMDs10. The inhibitory effect of these compounds was comparable to that of isoniazid, which is a first-line antituberculosis drug. The high antimycobacterial activity of KMD6, KMDs9 and KMDs10 was maintained on the experiment with M. tuberculosis. Of the active compounds identified, KMDs9 would be a promising pharmacophore, owing to its long-term antimycobacterial effect and lack of cytotoxicity.

    更新日期:2017-10-11
  • Synthetic studies of viridiofungins, broad-spectrum antifungal agents and serine palmitoyl transferase inhibitors
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Naoya Kumagai, Masakatsu Shibasaki

    Viridiofungins are alkyl citrate natural products characterized by their inhibitory effects on squalene synthase and serine palmitoyl transferase. Their activities as broad-spectrum antifungal agents as well as blocking agents for the biosynthesis of sphingolipids have inspired the development of several approaches toward their stereoselective total synthesis. Structurally, these natural products are a family of hybrid molecules comprising a longer alkyl chain and a citric acid unit, rendering an asymmetric structure that is difficult to access. Herein, we summarize the synthetic approaches to this attractive class of natural products, including proficient synthetic strategies for constructing the densely and chirally functionalized citric acid unit with high polarity. Particular emphasis is placed on methods for furnishing stereogenic centers in the highly constrained carbon framework.

    更新日期:2017-10-11
  • Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of β-lactams
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Neil PJ Price, Trina M Hartman, Jiakun Li, Kiran K Velpula, Todd A Naumann, Maheedhara R Guda, Biao Yu, Kenneth M Bischoff

    Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of β-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the β-lactams.

    更新日期:2017-10-11
  • Chemotherapeutics overcoming nonsense mutation-associated genetic diseases: medicinal chemistry of negamycin
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-27
    Akihiro Taguchi, Keisuke Hamada, Yoshio Hayashi

    Nonsense mutations caused by the presence of an in-frame premature termination codon (PTC) account for ~10% of gene lesions that together cause over 1800 inherited human diseases. One approach to treating genetic diseases that stem from PTCs is selective promotion of translational readthrough in a PTC using ‘readthrough compounds’ that can lead to partial restoration of full-length functional protein expression. (+)-Negamycin, a natural dipeptide-like antibiotic, may restore some dystrophin expression in the skeletal muscles of mice with Duchenne muscular dystrophy, and this compound has been recognized as a potential therapeutic agent for diseases caused by nonsense mutations. In an effort to develop new candidate molecules with improved activities, we established the efficient total synthesis in eight steps of (+)-negamycin using both achiral and chiral starting material. These routes provided a deamino derivative with in vivo readthrough activity with potential for long-term treatment. In a separate approach, we discovered two natural negamycin analogs, 3-epi-deoxynegamycin and its leucine derivative, which are potent readthrough compounds effective against nonsense mutations of eukaryotes but not prokaryotes. These compounds fail to display antimicrobial activity. More potent derivatives, whose structure is derived from 3-epi-deoxynegamycin, were identified and their chemistry is discussed in this review.

    更新日期:2017-10-11
  • Isolation of the antibiotic methyl (R,E)-3-(1-hydroxy-4-oxocyclopent-2-en-1-yl)-acrylate EA-2801 from Trichoderma atroviridae
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-20
    Emilie Adelin, Géraldine Le Goff, Pascal Retailleau, Mercedes Bonfill, Jamal Ouazzani

    The endophytic Trichoderma atroviridae UB-LMA was isolated as a symbiont of Taxus baccata and analyzed for its antimicrobial activity. By applying an original approach consisting of solid-state cultivation coupled with solid-phase extraction, a new methyl (R,E)-3-(1-hydroxy-4-oxocyclopent-2-en-1-yl)-acrylate derivative named EA-2801 (1) was isolated together with the previously reported isonitrin A and dermadin methyl ester. The chemical structure of 1 was determined by NMR and MS. Compound 1 showed antimicrobial activity against a panel of Gram-positive and -negative bacteria.

    更新日期:2017-09-21
  • Using experimental evolution to identify druggable targets that could inhibit the evolution of antimicrobial resistance
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-20
    Heer H Mehta, Amy G Prater, Yousif Shamoo

    With multi-drug and pan-drug-resistant bacteria becoming increasingly common in hospitals, antibiotic resistance has threatened to return us to a pre-antibiotic era that would completely undermine modern medicine. There is an urgent need to develop new antibiotics and strategies to combat resistance that are substantially different from earlier drug discovery efforts. One such strategy that would complement current and future antibiotics would be a class of co-drugs that target the evolution of resistance and thereby extend the efficacy of specific classes of antibiotics. A critical step in the development of such strategies lies in understanding the critical evolutionary trajectories responsible for resistance and which proteins or biochemical pathways within those trajectories would be good candidates for co-drug discovery. We identify the most important steps in the evolution of resistance for a specific pathogen and antibiotic combination by evolving highly polymorphic populations of pathogens to resistance in a novel bioreactor that favors biofilm development. As the populations evolve to increasing drug concentrations, we use deep sequencing to elucidate the network of genetic changes responsible for resistance and subsequent in vitro biochemistry and often structure determination to determine how the adaptive mutations produce resistance. Importantly, the identification of the molecular steps, their frequency within the populations and their chronology within the evolutionary trajectory toward resistance is critical to assessing their relative importance. In this work, we discuss findings from the evolution of the ESKAPE pathogen, Pseudomonas aeruginosa to the drug of last resort, colistin to illustrate the power of this approach.

    更新日期:2017-09-21
  • Hymerhabdrin A, a novel diterpenoid with antifouling activity from the intertidal sponge Hymerhabdia sp.
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-20
    Sheng-Tao Fang, Bing-Fei Yan, Cui-Yun Yang, Feng-Ping Miao, Nai-Yun Ji

    Hymerhabdrin A (1), a diterpenoid possessing a novel 6/6/5 fused-ring skeleton, together with four known sterols were isolated from an intertidal marine sponge Hymerhabdia sp. Their structures were elucidated by extensive spectroscopic methods, and the relative and absolute configurations of 1 were determined by NOESY analysis and electronic circular dichrosim calculations, respectively. Hymerhabdrin A (1) exhibited significant antifouling activity against Balanus amphitrite larval with LC50 (lethal concentration 50) value of 3.6 μg ml−1.

    更新日期:2017-09-21
  • Wakodecalines A and B, new decaline metabolites isolated from a fungus Pyrenochaetopsis sp. RK10-F058
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-13
    Toshihiko Nogawa, Naoki Kato, Takeshi Shimizu, Akiko Okano, Yushi Futamura, Shunji Takahashi, Hiroyuki Osada

    Two new decaline metabolites, wakodecalines A and B, were isolated from a fungus, Pyrenochaetopsis sp. RK10-F058, by screening for structurally unique metabolites using LC/MS analysis. Their structures were determined on the basis of NMR and mass spectrometric measurements. The absolute structures were confirmed by a combination of chemical methods including chemical degradation, a modified Mosher’s method and Marfey’s method, and comparison of the experimental electronic CD (ECD) spectrum with calculated one. Both compounds had a cyclopentanone-fused decaline skeleton and an N-methylated amino acid moiety derived from a serine. They showed moderate antimalarial activity against the Plasmodium falciparum 3D7 strain.

    更新日期:2017-09-13
  • Autophagy-regulating protease Atg4: structure, function, regulation and inhibition
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-13
    Tatsuro Maruyama, Nobuo N Noda

    Autophagy is an intracellular degradation system that contributes to cellular homeostasis through degradation of various targets such as proteins, organelles and microbes. Since autophagy is related to various diseases such as infection, neurodegenerative diseases and cancer, it is attracting attention as a new therapeutic target. Autophagy is mediated by dozens of autophagy-related (Atg) proteins, among which Atg4 is the sole protease that regulates autophagy through the processing and deconjugating of Atg8. As the Atg4 activity is essential and highly specific to autophagy, Atg4 is a prospective target for developing autophagy-specific inhibitors. In this review article, we summarize our current knowledge of the structure, function and regulation of Atg4 including efforts to develop Atg4-specific inhibitors.

    更新日期:2017-09-13
  • Suppressive drug combinations and their potential to combat antibiotic resistance
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-06
    Nina Singh, Pamela J Yeh

    Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called ‘suppressive interactions’ in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine the applicability of suppressive interactions in the clinic.

    更新日期:2017-09-06
  • Inhibitory effect of obovatol from Magnolia obovata on the Salmonella type III secretion system
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-06
    Won-Sik Choi, Tae Hun Lee, Se Jin Son, Tae Gyu Kim, Byoung-Mog Kwon, Hyeong-U Son, Sung Uk Kim, Sang-Han Lee

    In many pathogenic Gram-negative bacteria, such as Salmonella, Escherichia coli, Yersinia and Chlamydia spp., which cause diseases in humans, the type III secretion system (TTSS) is an important virulence factor that translocates effector proteins into the cytosol of host cells. Thus, the TTSS is a good target for antibacterial agents. Here we used a hemolysis assay to search for TTSS inhibitors and found that a compound from Magnolia obovata called obovatol blocks the TTSS of Salmonella. Obovatol showed potent inhibitory activity (IC50=19.8 μM) against the TTSS-related hemolysis of Salmonella, which was not due to a reduction of bacterial growth. Instead, the compound inhibited bacterial motility, TTSS-related mRNA expression and effector protein secretion. These data demonstrate the inhibitory effect of obovatol on the Salmonella TTSS and suggest that it could be useful for the prevention and supplementary treatment of bacterial infections.

    更新日期:2017-09-06
  • Structures and biological activities of novel 4’-acetylated analogs of chrysomycins A and B
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-06
    Shun-ichi Wada, Ryuichi Sawa, Fumiki Iwanami, Miho Nagayoshi, Yumiko Kubota, Kiyoko Iijima, Chigusa Hayashi, Yuko Shibuya, Masaki Hatano, Masayuki Igarashi, Manabu Kawada

    Two new 4’-acetylated analogs of chrysomycin were discovered during the screening for antitumor agents from the metabolites of actinomycetes. Their structures and physicochemical properties were determined by standard spectrometric analyses. Their cytotoxicities and antimicrobial activities were evaluated against a panel of cancer cell lines and microbes. While acetylation reinforced the cytotoxicity of chrysomycin B, it weakened the activity of chrysomycin A. Chrysomycin A and its acetylated analog showed high cytotoxicity toward most of the cancer cells with IC50s less than 10 ng ml−1. The 4’-acetyl-chrysomycin A was predominantly observed in nuclei at concentrations where the autofluorescence was observable. Chrysomycins were effective toward Gram-positive bacteria. The 4’-acetylated-chrysomycin A and B had MICs of 0.5–2 μg ml−1 and 2 to greater than 64 μg ml−1, respectively, toward Gram-positive bacteria including MRSA and VRE.

    更新日期:2017-09-06
  • A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-06
    Masatomi Iijima, Yuji Kubota, Ryuichi Sawa, Yumiko Kubota, Masaki Hatano, Masayuki Igarashi, Manabu Kawada, Isao Momose, Mutsuhiro Takekawa, Masakatsu Shibasaki

    Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63-43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5-cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.

    更新日期:2017-09-06
  • Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core
    J. Antibiot. (IF 2.237) Pub Date : 2017-09-06
    Douglas Charles Duquette, Thomas Jensen, Brian Mark Stoltz

    The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.

    更新日期:2017-09-06
  • Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-30
    Yike Zou, Amos B. Smith, III

    Indole terpenes have attracted the interests of synthetic chemists due to their complex architectures and potent biological activities. Examples of total syntheses of several indole terpenes were reviewed in this article to honor Professor KC Nicolaou.

    更新日期:2017-09-04
  • Novel approaches for identification of anti-tumor drugs and new bioactive compounds
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-30
    Manabu Kawada, Sonoko Atsumi, Shun-ichi Wada, Shuichi Sakamoto

    Thanks to the pioneering work done by Professor Hamao Umezawa, bioactive compounds have been used in treatment of several diseases including cancer. In this review, we discuss our work, which focuses on developing new candidates for anti-tumor drugs by screening for bioactive natural compounds in microbial cultures using unique experimental systems. We summarize our recent progress including the following: (1) small-molecule modulators of tumor–stromal cell interactions, (2) inhibitors of three-dimensional spheroid formation of cancer cells, (3) multi-cancer cell panel screening and (4) new experimental animal models for cancer metastasis.

    更新日期:2017-09-04
  • Corrigendum: γ-Ionylidene-type sesquiterpenoids possessing antimicrobial activity against Porphyromonas gingivalis from Phellinus linteus and their absolute structure determination
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-01
    Tatsuya Shirahata, Chieko Ino, Fumi Mizuno, Yoshihisa Asada, Masao Hirotani, George A Petersson, Satoshi Ōmura, Takafumi Yoshikawa, Yoshinori Kobayashi

    Correction to: The Journal of Antibiotics (2017) 70, 695–698. doi:10.1038/ja.2017.35, Published online 22 March 2017

    更新日期:2017-09-04
  • Engineered production and evaluation of 6′-deoxy-tallysomycin H-1 revealing new insights into the structure–activity relationship of the anticancer drug bleomycin
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-23
    Dong Yang, Hindra, Liao-Bin Dong, Ivana Crnovcic, Ben Shen

    The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure–activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM–TLM–ZBM hybrid metabolite, named 6′-deoxy-TLM H-1, which consists of the 22-desmethyl-BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus ΔtlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6′-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.

    更新日期:2017-09-04
  • A new anthracycline-type metabolite from Streptomyces sp. NEAU-L3
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-16
    Chang Lu, Yue Zhao, Wei-Qi Jia, Hui Zhang, Huan Qi, Wen-Sheng Xiang, Ji-Dong Wang, Xiang-Jing Wang

    A new anthracycline-type metabolite, designated as tetracenoquinocin A (1), was isolated from the fermentation broth of Streptomyces sp. NEAU-L3. Its structure was determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Compound 1 showed potent cytotoxic activity against three cancer cell lines (HepG2, A549, HCT-116) with IC50 values of 5.57, 24.30 and 20.82 μM, respectively.

    更新日期:2017-09-04
  • F-36316 A and B, novel vasoactive compounds, isolated from Incrucipulum sp. SANK 10414
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-09
    Yuki Hirota-Takahata, Yoko Ishimoto, Emi Kurosawa, Yuko Iwadate, Yoshiko Onozawa, Isshin Tanaka, Masahiro Tanaka, Hideki Kobayashi

    In the course of our screening program for vasoactive compounds using co-culture assay of endothelial cells and fibroblast cells, potent activity was detected in the cultured broth of Incrucipulum sp. SANK 10414. Two active compounds, F-36316 A and B, and a non-active homolog, F-36316 C, were isolated from the broth. The structures of F-36316 A, B and C were elucidated by physicochemical data and spectral analyses, and found to be new 3-acylated tetronic acid homologs. F-36316 A and B induced morphological changes of endothelial cells different from vascular endothelial growth factor (VEGF) or vestaines in the assay with EC50 values of 1.8 and 11.7 μM, respectively. Furthermore, F-36316 A and B suppressed VEGF-induced vascular permeability induction in mice.

    更新日期:2017-09-04
  • Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-02
    Alasdair TM Hubbard, Anthony RM Coates, Richard D Harvey

    HT61 and chlorhexidine (CHX) are both putative membrane-active antimicrobials, which non-specifically target the anionic lipids abundant in bacterial membranes. In model systems, the ability of these antimicrobials to partition into lipid monolayers and increase the permeability of lipid bilayers is dependent upon the presence and proportion of anionic lipids such as phosphatidylglycerol. Despite their apparent similarity in membrane affinity, we have found that HT61 and CHX differ in the extent to which they affect membrane integrity. HT61 was found to be capable of severely disrupting the lipid bilayer, resulting in lysis of Staphylococcus aureus membranes and the release of ATP from protoplasts. CHX, by contrast, does not disrupt the lipid bilayer to a sufficiently large degree to result in lysis of the membrane or release of ATP from S. aureus protoplasts. This suggests that although antimicrobials that interact with the membrane often have a common target, the action they have on the membrane may differ widely and may not be the primary mode of action of the antimicrobial.

    更新日期:2017-09-04
  • Formal synthesis of englerin A utilizing regio- and diastereoselective [4+3] cycloaddition
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-02
    Shuichi Hagihara, Kengo Hanaya, Takeshi Sugai, Mitsuru Shoji

    Englerin A, a guaiane sesquiterpene isolated from Phyllanthus engleri, showed highly potent and selective growth inhibitory activities against renal cancer cell lines. We synthesized the key tricyclic intermediate from commercially available 2,2-dimethyl-1,3-dioxan-5-one via regio- and diastereoselective [4+3] cycloaddition between the formyl enol silyl ether and the disubstituted furan, in 4.8% total yield over 10 steps.

    更新日期:2017-09-04
  • Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-30
    Yike Zou, Amos B. Smith, III

    Indole terpenes have attracted the interests of synthetic chemists due to their complex architectures and potent biological activities. Examples of total syntheses of several indole terpenes were reviewed in this article to honor Professor KC Nicolaou.

    更新日期:2017-08-30
  • Novel approaches for identification of anti-tumor drugs and new bioactive compounds
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-30
    Manabu Kawada, Sonoko Atsumi, Shun-ichi Wada, Shuichi Sakamoto

    Thanks to the pioneering work done by Professor Hamao Umezawa, bioactive compounds have been used in treatment of several diseases including cancer. In this review, we discuss our work, which focuses on developing new candidates for anti-tumor drugs by screening for bioactive natural compounds in microbial cultures using unique experimental systems. We summarize our recent progress including the following: (1) small-molecule modulators of tumor–stromal cell interactions, (2) inhibitors of three-dimensional spheroid formation of cancer cells, (3) multi-cancer cell panel screening and (4) new experimental animal models for cancer metastasis.

    更新日期:2017-08-30
  • Trichopeptides A and B, trichocyclodipeptides A–C, new peptides from the ascomycete fungus Stagonospora trichophoricola
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Zhengkun Chen, Xiuli Xu, Jinwei Ren, Wenzhao Wang, Xingzhong Liu, Erwei Li

    Trichopeptides A (1) and B (2), new linear tetrapeptide and tripeptide, respectively, and three new diketopiperazines trichocyclodipeptides A–C (3–5) were isolated from the fermentation of the ascomycete fungus Stagonospora trichophoricola, a fungus isolated from the soil sample surrounding the fruiting body of Ophiocordyceps sinensis in Maqin Country, Qinghai Province, People’s Republic of China. Their structures were primarily elucidated by interpretation of NMR and MS experiments. The absolute configurations of 1–5 were assigned through Marfey’s method on their acid hydrolyzates. Compound 3 showed antifungal activity against Candida albicans with the IC50 and MIC values of 22 and 90 μg ml−1, respectively.

    更新日期:2017-08-28
  • Allantopyrone A interferes with multiple components of the TNF receptor 1 complex and blocks RIP1 modifications in the TNF-α-induced signaling pathway
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Hue Tu Quach, Riho Tanigaki, Junpei Yokoigawa, Yuriko Yamada, Masamitsu Niwa, Seiya Hirano, Yoshihito Shiono, Ken-ichi Kimura, Takao Kataoka

    Allantopyrone A is a fungal metabolite that uniquely possesses two α,β-unsaturated carbonyl moieties. We recently reported that allantopyrone A inhibited the nuclear factor-κB (NF-κB) signaling pathway induced by tumor necrosis factor (TNF)-α in human lung carcinoma A549 cells. In the present study, the mechanism by which allantopyrone A inhibits the TNF-α-induced signaling pathway was investigated in more detail. Allantopyrone A blocked extensive modifications to receptor-interacting protein 1 (RIP1) in the TNF receptor 1 (TNF-R1) complex. Allantopyrone A augmented the high-MW bands of TNF-R1, TNF receptor-associated factor 2, RIP1, the NF-κB subunit RelA and inhibitor of NF-κB kinase β in A549 cells, suggesting that it binds to and promotes the crosslinking of these proteins. The extracellular cysteine-rich domains of TNF-R1 were crosslinked by allantopyrone A more preferentially than its intracellular portion. The present results demonstrate that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-α-induced NF-κB signaling pathway.

    更新日期:2017-08-28
  • The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-07
    Pia Uusitalo, Ulrik Hägglund, Elin Rhöös, Henrik Scherman Norberg, Mikael Elofsson, Charlotta Sundin

    Pseudomonas aeruginosa is an opportunistic pathogen that can be very hard to treat because of high resistance to different antibiotics and alternative treatment regimens are greatly needed. An alternative or a complement to traditional antibiotic is to inhibit virulence of the bacteria. The salicylidene acylhydrazide, INP0341, belongs to a class of compounds that has previously been shown to inhibit virulence in a number of Gram-negative bacteria. In this study, the virulence blocking effect of INP0341 on P. aeruginosa was studied in vitro and in vivo. Two important and closely related virulence system were examined, the type III secretion system (T3SS) that translocates virulence effectors into the cytosol of the host cell to evade immune defense and facilitate colonization and the flagella system, needed for motility and biofilm formation. INP0341 was shown to inhibit expression and secretion of the T3SS toxin exoenzyme S (ExoS) and to prevent bacterial motility on agar plates and biofilm formation. In addition, INP0341 showed an increased survival of P. aeruginosa-infected mice. In conclusion, INP0341 attenuates P. aeruginosa virulence.

    更新日期:2017-08-28
  • Insight into synergetic mechanisms of tetracycline and the selective serotonin reuptake inhibitor, sertraline, in a tetracycline-resistant strain of Escherichia coli
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-12
    Lili Li, Sofie Kromann, John Elmerdahl Olsen, Søren Wedel Svenningsen, Rikke Heidemann Olsen

    Sertraline, an antidepressive drug, has been reported to inhibit general bacterial efflux pumps. In the present study, we report for the first time a synergistic effect of sertraline and tetracycline in a TetA-encoded tetracycline-resistant strain of Escherichia coli. Synergy between sertraline and tetracycline in an E. coli strain with TetA-mediated tetracycline resistance (E. coli APEC_O2) was assessed by the MIC and checkerboard assays. The global transcriptome of E. coli APEC_O2 exposed to ½ MIC concentrations of sertraline and/or tetracycline was analyzed to elucidate the interaction mechanism between sertraline and tetracycline. The fractional inhibitory concentration index for tetracycline and sertraline in E. coli APEC_O2 was 0.5. In addition, in the presence of ½ MIC of sertraline, the sensitivity of E. coli APEC_O2 to tetracycline could be restored according to clinical standards (from 64 to 4 mg l−1). RNA data suggest changes in respiration that is likely to decrease intracellular pH and thereby the proton-motive force, which provides the energy for the tetracycline efflux pump. Furthermore, sertraline and tetracycline may induce a change from oxidation to fermentation in the E.coli, which further decreases pH, resulting in cell death. This study shows that sertraline interacts with tetracycline in a synergistic and AcrAB-TolC pump-independent manner. The combinational treatment was further shown to induce many changes in the global transcriptome, including altered tetA and tetR expression. The results indicate that sertraline may be used as a helper compound with the aim to reverse tetracycline resistance encoded by tetA.

    更新日期:2017-08-28
  • Coumarin–benzimidazole hybrids as a potent antimicrobial agent: synthesis and biological elevation
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-21
    L Ravithej Singh, Srinivasa Rao Avula, Sneha Raj, Akanksha Srivastava, Gopala Reddy Palnati, C K M Tripathi, Mukesh Pasupuleti, Koneni V Sashidhara

    Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin–benzimidazole hybrids were designed, synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzo[d]imidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl)-2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. In addition, it has showed no cytotoxicity and hemolysis at 10 times the MIC concentration. SAR studies indicate that position of the chlorine atom in the hybrid critically determines the antibacterial activity.

    更新日期:2017-08-28
  • Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-14
    Fabrizio Angius, Enrica Piras, Sabrina Uda, Clelia Madeddu, Roberto Serpe, Rachele Bigi, Wuguo Chen, Dirk P Dittmer, Raffaello Pompei, Angela Ingianni

    Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, is the causative agent of Kaposi sarcoma; this malignant angiosarcoma is usually treated with conventional antitumor agents that can control disease evolution, but do not clear the latent KSHV episome that binds to cellular DNA. Some commercial antibacterial sulfonamides were tested for the ability to suppress latent KSHV. Quantitative PCR (qPCR) and cytofluorometry assays were used for detecting both viral DNA and the latency factor LANA (latency-associated nuclear antigen) in BC3 cells, respectively. The capacity of sulfonamides to impair MDM2–p53 complex formation was detected by an enzyme-linked immunosorbent assay method. The analysis of variance was performed according to one-way analysis of variance with Fisher as a post hoc test. Here we show that sulfonamide antibiotics are able to suppress the KSHV latent state in permanently infected BC3 lymphoma cells and interfere with the formation of the MDM2–p53 complex that KSHV seemingly needs to support latency and to trigger tumor cell transformation. These findings detected a new molecular target for the activity of sulfonamides and offer a new potential perspective for treating KSHV-induced lymphoproliferative diseases.

    更新日期:2017-08-28
  • A 2,4′-linked tetrahydroxanthone dimer with protein tyrosine phosphatase 1B inhibitory activity from the Okinawan freshwater Aspergillus sp.
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-28
    Henki Rotinsulu, Hiroyuki Yamazaki, Tomohito Miura, Satomi Chiba, Defny S Wewengkang, Deiske A Sumilat, Michio Namikoshi

    In the course of our research on protein tyrosine phosphatase (PTP) 1B inhibitors, we identified a new 2,4′-linked tetrahydroxanthone dimer (1), named secalonic acid F1 (Figure 1a) in the culture broth of the Okinawan freshwater fungus Aspergillus sp. TPU1343.

    更新日期:2017-08-28
  • NC1404, a novel derivative of Bleomycin with modified sugar moiety obtained during the preparation of Boningmycin
    J. Antibiot. (IF 2.237) Pub Date : 2017-05-31
    Xin Qi, Xinwei Wang, Hao Ren, Feng Zhang, Xiumin Zhang, Ning He, Wenqiang Guo, Ruxian Chen, Yunying Xie, Qiyang He

    Boningmycin, isolated from the fermentation broth of Streptomyces verticillus var. pingyangensis n.

    更新日期:2017-08-28
  • Effect of the meropenem MIC on the killing activity of meropenem and polymyxin B in combination against KPC-producing Klebsiella pneumoniae
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Brandon Kulengowski, Jeffrey J Campion, David J Feola, David S Burgess

    Infections caused by multidrug resistant Klebsiella pneumoniae that produce K. pneumoniae carbapenemase (KPC) typically require treatment with two or more antimicrobial agents. Although carbapenems are hydrolyzed by KPCs, combined therapy with a carbapenem and a polymyxin (colistin or polymyxin B) significantly lowers mortality in critically ill patients infected with polymyxin-susceptible K. pneumoniae

    更新日期:2017-08-28
  • Engineered production and evaluation of 6′-deoxy-tallysomycin H-1 revealing new insights into the structure–activity relationship of the anticancer drug bleomycin
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-23
    Dong Yang, Hindra, Liao-Bin Dong, Ivana Crnovcic, Ben Shen

    The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure–activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM–TLM–ZBM hybrid metabolite, named 6′-deoxy-TLM H-1, which consists of the 22-desmethyl-BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus ΔtlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6′-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.

    更新日期:2017-08-23
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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