显示样式:     当前分类: 医药    当前期刊: The Journal of Antibiotics    加入关注    导出
我的关注
我的收藏
您暂时未登录!
登录
  • 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
  • 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:2017-08-16
  • 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:2017-08-09
  • 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:2017-08-02
  • 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:2017-08-02
  • Rakicidin F, a new antibacterial cyclic depsipeptide from a marine sponge-derived Streptomyces sp.
    J. Antibiot. (IF 2.237) Pub Date : 2017-08-02
    Shigeru Kitani, Tatsuya Ueguchi, Yasuhiro Igarashi, Kantinan Leetanasaksakul, Arinthip Thamchaipenet, Takuya Nihira

    A new cyclic depsipeptide, rakicidin F (1), along with the known compound rakicidin C (2), was isolated from the fermentation broth of the marine sponge-derived actinomycete strain Streptomyces sp. GKU 220. Their structures were elucidated by interpreting the HRFABMS and NMR spectroscopic data. Rakicidin F (1) showed growth inhibitory activity against bacteria.

    更新日期:2017-08-02
  • Heterocyclyl tetracyclines. 2. 7-Methoxy-8-pyrrolidinyltetracyclines: discovery of TP-2758, a potent, orally efficacious antimicrobial against Gram-negative pathogens
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-26
    Cuixiang Sun, Yonghong Deng, Diana K Hunt, Corey Fyfe, Chi-Li Chen, Roger B Clark, Trudy H Grossman, Joyce A Sutcliffe, Xiao-Yi Xiao

    A convergent total synthesis platform led to the discovery of TP-2758 from a series of novel 7-methoxy-8-heterocyclyl tetracycline analogs. TP-2758 demonstrated high in vitro potency against key Gram-negative pathogens including extended spectrum β-lactamases- and carbapenemase-producing Enterobacteriaceae and Acinetobacter spp. strains. This compound was efficacious when administered either intravenously or orally in multiple murine infection models and displayed a favorable preclinical pharmacological profile supporting its advancement into clinical development.

    更新日期:2017-07-29
  • Synthesis of unique spirocyclic orthoester-type derivatives of isothiazolo[4,3-d]pyrimidine nucleosides
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-26
    Alexander R Rovira, Yitzhak Tor

    A set of unique nucleoside analogs, containing ‘spirocyclic orthoester-type’ scaffolds, were synthesized from a common isothiazolo[4,3-d]pyrimidine-riboside precursor. The key reaction, using 1,2-di-heteroatomic nucleophiles (e.g., 1,2-ethandithiol) and BF3•OEt2, converts an exocyclic imine into the spirocyclic analogs. The novel structural scaffold is confirmed through the use of one- and two-dimensional 1H and 13C NMR experiments.

    更新日期:2017-07-29
  • In vivo efficacy of β-lactam/tripropeptin C in a mouse septicemia model and the mechanism of reverse β-lactam resistance in methicillin-resistant Staphylococcus aureus mediated by tripropeptin C
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-26
    Hideki Hashizume, Yoshiaki Takahashi, Tohru Masuda, Shun-ichi Ohba, Tomokazu Ohishi, Manabu Kawada, Masayuki Igarashi

    Natural lipopeptide antibiotic tripropeptin C (TPPC) revitalizes and synergistically potentiates the activities of the class of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) but not against methicillin-sensitive S. aureus in vitro; however, the mode of action remains unclear. In the course of the study to reveal its mode of action, we found that TPPC inhibited the β-lactamase production induced by cefotiam. This prompted us to focus on the β-lactam-inducible β-lactam-resistant genes blaZ (β-lactamase) and mecA (foreign penicillin-binding protein), as they are mutually regulated by the blaZ/I/R1 and mecA/I/R1 systems. Quantitative reverse-transcription polymerase chain reaction analysis revealed that TPPC reversed β-lactam resistance by reducing the expression of the genes blaZ and mecA, when treated alone or in combination with β-lactam antibiotics. In a mouse/MRSA septicemia model, subcutaneous injection of a combination of TPPC and ceftizoxime demonstrated synergistic therapeutic efficacy compared with each drug alone. These observations strongly suggested that reverse β-lactam resistance by TPPC may be a potentially effective new therapeutic strategy to overcome refractory MRSA infections.

    更新日期:2017-07-29
  • Total synthesis of (+)-lysergic acid
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-19
    Rentaro Kanno, Satoshi Yokoshima, Motomu Kanai, Tohru Fukuyama

    A total synthesis of (+)-lysergic acid, which features the C–C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.

    更新日期:2017-07-29
  • Allostreptomyces indica sp. nov., isolated from India
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-19
    Amit Kumar Sahu, Syed Raziuddin Quadri, Dayanand Agasar, Jamal Al Ruwaili, Wen Jun-Li, Syed G Dastager

    A novel actinobacterium, designated strain YIM 75704T, was isolated from a limestone quarry located at Gulbarga, Karnataka, India. The novel strain has showed typical morphological and chemotaxonomic characteristics of the family Streptomycetaceae. Comparison of 16S rRNA gene sequences indicated that this strain represents a novel member of the family Streptomycetaceae and exhibited 99.0% 16S rRNA gene sequence similarities with the type species of the recently described novel genus Allostreptomyces, that is, Allostreptomyces psammosilenae, whereas other species of Streptomyces were below 95% sequence similarity. The cell hydrolysates contained the LL-isomer of diaminopimelic acid and the predominant quinones were MK-9 (H6, H8 and H4). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylinositolmannosides and three unknown phospholipids. The DNA G+C content was 75.0 mol%. A polyphasic study of the strain with morphological, phenotypic, phylogenetic and with DNA–DNA hybridization evidence with related members showed that this strain represents novel species of Allostreptomyces for which the name Allostreptomyces indica sp. nov., is proposed. The type strain is YIM 75704T (= DSM 41985T=CCTCC AA 209051T= NCIM 5485T).

    更新日期:2017-07-29
  • Novel p-terphenyl glycoside with a rare 2,6-dideoxyhexopyranose moiety from Actinomycete strain SF2911 that inhibits cancer cell migration
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-19
    Liyan Wang, Menjie Li, Jianqiang Tang, Yinzhi Lin, Kulrawee Sidthipong, Naomi Sumida, Nobuaki Kushida, Kazuo Umezawa

    In the course of our search for inhibitors of LPS-induced NO production from microbial strains, an ethyl acetate extract of Actinomycete SF2911, isolated from a soil sample collected in Okinawa Prefecture, Japan, showed the inhibitory activity. The active principle was purified and structure determination led to the isolation of one new compound. Since the structure belongs to the terfestatin family, we named it terfestatin D (1). It was found to inhibit cellular migration of breast carcinoma cells as well as NO production. We herein report the isolation, structure elucidation and biological activities of this new compound.

    更新日期:2017-07-29
  • Discovering potential Streptomyces hormone producers by using disruptants of essential biosynthetic genes as indicator strains
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-19
    Nguyen B Thao, Shigeru Kitani, Hiroko Nitta, Toshiya Tomioka, Takuya Nihira

    Autoregulators are low-molecular-weight signaling compounds that control the production of many secondary metabolites in actinomycetes and have been referred to as ‘Streptomyces hormones’. Here, potential producers of Streptomyces hormones were investigated in 40 Streptomyces and 11 endophytic actinomycetes. Production of γ-butyrolactone-type (IM-2, VB) and butenolide-type (avenolide) Streptomyces hormones was screened using Streptomyces lavendulae FRI-5 (ΔfarX), Streptomyces virginiae (ΔbarX) and Streptomyces avermitilis (Δaco), respectively. In these strains, essential biosynthetic genes for Streptomyces hormones were disrupted, enabling them to respond solely to the externally added hormones. The results showed that 20% of each of the investigated strains produced IM-2 and VB, confirming that γ-butyrolactone-type Streptomyces hormones are the most common in actinomycetes. Unlike the γ-butyrolactone type, butenolide-type Streptomyces hormones have been discovered in recent years, but their distribution has been unclear. Our finding that 24% of actinomycetes (12 of 51 strains) showed avenolide activity revealed for the first time that the butenolide-type Streptomyces hormone is also common in actinomycetes.

    更新日期:2017-07-29
  • New 12,8-Eudesmanolides from Eutypella sp. 1–15
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-19
    Yuezhou Wang, Yue Wang, An-an Wu, Lei Zhang, Zhiyu Hu, Huiying Huang, Qingyan Xu, Xianming Deng

    Four new 12,8-Eudesmanolides (1−4) and one known compound 5 named 13-Hydroxy-3,7(11)-eudesmadien-12,8-olide, were isolated from a mangrove rhizosphere-derived fungus Eutypella sp. 1–15. Their structures with absolute stereochemistry were determined by the comprehensive spectroscopic data, experimental and calculated ECD analysis. Compound 1 exhibited potent anticancer activity against JEKO-1 and HepG2 with IC50 values of 8.4 and 28.5 μM, respectively. Additionally, compound 1 also showed moderate antimicrobial activity.

    更新日期:2017-07-29
  • New anti-inflammatory metabolites produced by Streptomyces violaceoruber isolated from Equus burchelli feces
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-12
    Jian Ma, Hui Lei, Xiu Chen, Xiaoxu Bi, Yi Jiang, Li Han, Xueshi Huang

    Three new metabolites (2–4), together with one known compound, GTRI-02, (1) were isolated from a fermentation broth of Streptomyces violaceoruber derived from Equus burchelli feces. The structures of the new compounds 2–4 were established using comprehensive NMR spectroscopic data analysis as well as UV, IR and MS data. The anti-inflammatory activity of compounds 1–4 was tested by examining their ability to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Compound 2 showed a moderate inhibition of NO production with IC50 value of 51.2 μm.

    更新日期:2017-07-29
  • 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:2017-07-29
  • A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-12
    Dhanalakshmi R Nair, Ji Chen, João M Monteiro, Michaele Josten, Mariana G Pinho, Hans-Georg Sahl, Jimmy Wu, Ambrose Cheung

    In a loss-of-viability screen of small molecules against methicillin-resistant Staphylococcus aureus (MRSA) USA300, we found a small molecule, designated DNAC-2, which has an MIC of 8 μg ml−1. DNAC-2 is a quinolinol derivative that is bactericidal at 2X MIC. Macromolecular synthesis assays at 2 × MIC of DNAC-2 revealed inhibition of DNA, cell wall, RNA and protein synthesis within fifteen to thirty minutes of treatment when compared to the untreated control. Transmission electron microscopy of DNAC-2-treated cells revealed a significantly thicker cell wall and impaired daughter cell separation. Exposure of USA300 cells to 1 × MIC of DNAC-2 resulted in mislocalization of PBP2 away from the septum in an FtsZ-independent manner. In addition, membrane localization with FM4–64, as well as depolarization study with DiOC2 and lipophilic cation TPP+ displayed membrane irregularities and rapid membrane depolarization, respectively, in DNAC-2-treated cells vs -untreated control. However, DNAC-2 exhibited almost no toxicity toward eukaryotic membranes. Notably, DNAC-2 drives energy generation toward substrate level phosphorylation and the bacteria become more sensitive to DNAC-2 under anaerobic conditions. We propose that DNAC-2 affects USA300 by targeting the membrane, leading to partial membrane depolarization and subsequently affecting aerobic respiration and energy-dependent functional organization of macromolecular biosynthetic pathways. The multiple effects may have the desirable consequence of limiting the emergence of resistance to DNAC-2.

    更新日期:2017-07-29
  • Virgisporangium myanmarense sp. nov., a novel motile actinomycete isolated from an anthill soil in Myanmar
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-12
    Hideki Yamamura, Shoya Miyazaki, Kodai Ikoma, Youji Nakagawa, Moriyuki Hamada, Misa Otoguro, Tomohiko Tamura, Katsuhiko Ando, Nyunt Phay, Masayuki Hayakawa

    An actinomycete strain, designated MM04-1133T, was isolated from an anthill soil sample collected in Bagan, Myanmar. To establish the taxonomic status of this strain, the isolate was subjected to a polyphasic approach. Strain MM04-1133T was Gram-staining positive, aerobic, motile and formed long and narrow sporangia directly above the surface of the substrate mycelium. Whole-cell hydrolysates of the strain contained 3-OH-diaminopimelic acid, arabinose, glucose, galactose, mannose, rhamnose and xylose. The predominant menaquinones were MK-10(H6) and MK-10(H8). The major cellular fatty acids were iso-C16:0 and anteiso-C17:0. The diagnostic phospholipid was phosphatidylethanolamine. The G+C content of the DNA was 69.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequence revealed that strain MM04-1133T clustered within the genus Virgisporangium, with the sequence exhibiting highest similarity (98.5% identity) with Virgisporangium ochraceum NBRC 16418T. The strain grew in the presence of 0–1% (w/v) NaCl, at pH 5–8 and at 20–40 °C, with optimal growth at 30–37 °C. Based on phylogenetic analysis and chemotaxonomic and phenotypic data, we propose classifying this isolate as a novel species of the genus Virgisporangium, to be designated as Virgisporangium myanmarense sp. nov. The type strain is MM04-1133T (=NBRC 112733T=VTCC 910008T).

    更新日期:2017-07-29
  • Synthesis and antibacterial activity of novel lincomycin derivatives. III. Optimization of a phenyl thiadiazole moiety
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Ko Kumura, Yoshinari Wakiyama, Kazutaka Ueda, Eijiro Umemura, Takashi Watanabe, Mikio Yamamoto, Takuji Yoshida, Keiichi Ajito

    Lincomycin derivatives that have a 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl thio moiety at the 7-position were synthesized. 5-Substituted 2-nitrophenyl derivatives showed potent antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene. Antibacterial activities of the 4,5-di-substituted 2-nitrophenyl derivatives were generally comparable to those of telithromycin (TEL) against S. pneumoniae with erm gene and clearly superior to those of TEL against S. pyogenes with erm gene. Compounds 6 and 10c that have a methoxy group at the 5-position of the benzene ring exhibited activities comparable to TEL against Haemophilus influenzae. These results suggest that lincomycin derivatives modified at the 7-position would be promising compounds as a clinical candidate. We would like to dedicate this article to the special issue for late Professor Dr. Hamao Umezawa in The Journal of Antibiotics.

    更新日期:2017-07-29
  • A brief history of antibiotics and select advances in their synthesis
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Kyriacos C Nicolaou, Stephan Rigol

    The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against these pathogens, the war against them has not been won. And it may never be. Drug resistance is still menacing the society with many lives being lost due to deadly infections caused by continuously evolving strains spread beyond our means to eradicate them or prevent their spreading. Herein, the emergence and evolution of antibiotics is briefly reviewed, and a select number of total syntheses of naturally occurring antibiotics from the authors’ laboratories are highlighted. The article concludes with a strong endorsement of the current efforts to intensify our fight against these dangerous pathogens with the hope that, this time, these initiatives will be sufficiently focused and serious enough so as to achieve our set goals of, at least, being prepared and ahead of them as part of our drive to improve humanity’s healthcare and wellbeing.

    更新日期:2017-07-29
  • 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:2017-07-29
  • 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:2017-07-29
  • 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:2017-07-29
  • Toward the total synthesis of luminamicin; an anaerobic antibiotic: construction of highly functionalized cis-decalin containing a bridged ether moiety
    J. Antibiot. (IF 2.237) Pub Date : 2017-07-05
    Hiroyasu Ando, Aoi Kimishima, Motoyoshi Ohara, Tomoyasu Hirose, Takanori Matsumaru, Hirokazu Takada, Keisuke Morodome, Takehiro Miyamoto, Akihiro Sugawara, Satoshi Ōmura, Toshiaki Sunazuka

    Synthesis of a cis-decalin moiety, containing an oxa-bridged cis-decalin ring system (11-oxatricyclo(5.3.1.1,703,8)undecane), as a key intermediate of the total synthesis of luminamicin (1) was accomplished. One of the essential steps in our synthetic route is construction of a cis-decaline framework using a one-pot Michael addition-aldol reaction. Additionally, the bridged ether moiety was obtained by an intramolecular 1,6-oxa-Michael reaction of a conjugated aldehyde.

    更新日期:2017-07-29
  • Discovery of 2-hydroxyarbekacin, a new aminoglycoside antibiotic with reduced nephrotoxicity
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-28
    Yoshiaki Takahashi, Eijiro Umemura, Yoshihiko Kobayashi, Shoichi Murakami, Toru Nawa, Akihiro Morinaka, Toshiaki Miyake, Masakatsu Shibasaki

    The emergence and spread of bacteria with resistance to antibacterial drugs in recent years is now considered a significant threat to global public health and the world economy.1, 2 In particular, the severe bacterial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa have become serious clinical problems because of increased antimicrobial resistance, as observed for vancomycin-resistant S. aureus and multi-drug resistant P. aeruginosa

    更新日期:2017-07-29
  • 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:2017-07-29
  • 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:2017-07-29
  • 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:2017-07-29
  • A three-component coupling approach to the ACE-ring substructure of C19-diterpene alkaloids
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-14
    Kosuke Minagawa, Daisuke Urabe, Masayuki Inoue

    C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component coupling strategy. A radical–polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an aldehyde was realized by the actions of Et3B and O2, resulting in the installation of three new stereocenters and extension of the carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons, 4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.

    更新日期:2017-07-29
  • 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:2017-07-29
  • Albiducins A and B, salicylaldehyde antibiotics from the ash tree-associated saprotrophic fungus Hymenoscyphus albidus
    J. Antibiot. (IF 2.237) Pub Date : 2017-06-07
    Sandra Halecker, Frank Surup, Halvor Solheim, Marc Stadler

    Since the early 1990s, European ash (Fraxinus excelsior) has been facing an onslaught of severe dieback in most of its natural distribution area in Europe. The causal agent of this epidemic disease is the invasive ascomycete Hymenoscyphus fraxineus (=Hymenoscyphus pseudoalbidus). This fungal pathogen most probably originates from East Asia and has almost replaced the European sister species Hymenoscyphus albidus. The latter species, H. albidus

    更新日期:2017-07-29
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.
所有期刊列表A-Z