Dolyemycins A and B, two novel cyclopeptides isolated from Streptomyces griseus subsp. griseus HYS31 J. Antibiot. (IF 2.033) Pub Date : 2018-07-06 Xiao-dong Liu, Kang-bo Gu, Sha-Sha Xia, Dao-Jing Zhang, Yuan-Guang Li
Two novel cyclopeptides with special skeleton, namely, dolyemycins A (1) and B (2) were isolated from Streptomyces griseus subsp. griseus HYS31 by bio-guided isolation. Their structures were elucidated by detailed analysis of spectroscopic data. These two compounds were cyclopeptides containing eleven amino acids including five unusual amino acids (hydroxyglycine, 3-hydroxyleucine, 3-phenylserine, β-hydroxy-O-methyltyrosine, 2,3-diaminobutyric acid) in both of them and an extra nonprotein amino acids (3-methylaspartic acid) in Dolyemycin B only. Dolyemycins A and B performed antiproliferative activity against human lung cancer A549 cells with IC50 values of 1.0 and 1.2 µM, respectively.
Identification of a novel bacteriocin-like protein and structural gene from Rhodococcus erythropolis JCM 2895, using suppression-subtractive hybridization J. Antibiot. (IF 2.033) Pub Date : 2018-07-06 Wataru Kitagawa, Shinya Mitsuhashi, Miyako Hata, Tomohiro Tamura
A novel bacteriocin-like protein and its structural gene (rap) were identified from Rhodococcus erythropolis JCM 2895. The rapA and B genes are located on a 5.4-kb circular plasmid, and were obtained using a modified suppression-subtractive hybridization method. The rapA and B genes were heterologously expressed in Rhodococcus sp. or Escherichia coli, and then characterized. The results indicated that RapA is a small, water-soluble, heat-stable antimicrobial protein, and that RapB is an immunity protein against RapA, estimated to be located on the cell membrane. RapA showed antimicrobial activity particularly against R. erythropolis, and the activity persisted even after SDS-PAGE analysis. For the heterologous expressed RapA protein, N-terminal amino acid sequence was also confirmed. This is the first report of a bacteriocin-like substance obtained from the genus Rhodococcus.
Peniazaphilin A, a new azaphilone derivative produced by Penicillium sp. CPCC 400786 J. Antibiot. (IF 2.033) Pub Date : 2018-07-05 Dewu Zhang, Jianyuan Zhao, Xinwei Wang, Lili Zhao, Hongyu Liu, Yuzhen Wei, Xuefu You, Shan Cen, Liyan Yu
A new azaphilone derivative, named peniazaphilin A (1) and one known isocoumarin, (R)-3-methyl-6-hydroxy-8-methoxy-3,4-dihydroisocoumarin (2) were isolated from the fungus Penicillium sp. CPCC 400786. Their structures were elucidated by means of extensive spectroscopic analysis. The absolute configuration of 2 was established by circular dichroism for the first time. Compounds 1 and 2 exhibited weak anti-HIV activities with the IC50 values of 60.4 and 69.3 μM, respectively.
Asperitaconic acids A–C, antibacterial itaconic acid derivatives produced by a marine-derived fungus of the genus Aspergillus J. Antibiot. (IF 2.033) Pub Date : 2018-07-04 Lijian Ding, Te Li, Xiaojian Liao, Shan He, Shihai Xu
Three new itaconic acid derivatives, asperitaconic acids A–C (1–3), were isolated from the ethyl acetate extracts of the rice fermentation of a marine-derived fungus Aspergillus niger, and asperitaconic acids A–C were characterized by an itaconic acid unit and an alkyl chain moiety. Their structures were established by interpretation of their spectroscopic data including NMR and HRESIMS. Asperitaconic acids A–C exhibited antibacterial effect against Staphylococcus aureus with MIC values of 16–32 μg/mL, whereas these compounds showed no cytotoxicity against HepG2 and HeLa cancer cell lines.
Engineered production of kitasetalic acid, a new tetrahydro-β-carboline with the ability to suppress glucose-regulated protein synthesis J. Antibiot. (IF 2.033) Pub Date : 2018-07-04 Shohei Ueda, Shigeru Kitani, Takushi Namba, Masayoshi Arai, Haruo Ikeda, Takuya Nihira
β-Carboline alkaloids and related compounds show a broad spectrum of biological activities. We previously identified new members of the β-carboline alkaloid family by using an engineered Kitasatospora setae strain and a heterologous Streptomyces host expressing the plausible biosynthetic genes, including the hypothetical gene kse_70640 (kslB). Here, we elucidated the chemical structure of a new tetrahydro-β-carboline compound (named kitasetalic acid) that appeared in a heterologous Streptomyces host expressing the kslB gene alone. Kitasetalic acid suppressed the expression of glucose-regulated protein 78 (GRP78) without inducing cell death. This is the first report to show that a tetrahydro-β-carboline compound regulates the expression of the GRP78 protein in cancer cell lines.
Discovery of hybrids of indolin-2-one and nitroimidazole as potent inhibitors against drug-resistant bacteria J. Antibiot. (IF 2.033) Pub Date : 2018-07-03 Yuanzheng Zhou, Yuan Ju, Yang Yang, Zitai Sang, Zhenling Wang, Gu He, Tao Yang, Youfu Luo
With antibiotics resistance developing rapidly, new antibacterial agents are needed to be discovered. We readily synthesized 11 indolin-2-one compounds and found a hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)indolin-2-one to be effective on Staphylococcus aureus strains. Six derivatives of this compound were further designed and synthesized in order to enhance its efficacy. After a second turn of structural refinement, a novel hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)-5-nitroindolin-2-one with a nitro group on C-5 position of indolin-2-one was shown to exhibit remarkable antibacterial activities with a low MIC value against MRSA ATCC 33591. Besides, this molecule demonstrated its potency on Gram-negative bacteria and VRE strain. The time-killing curve experiment showed its good bactericidal activity. Low hemolytic rate suggested its promising safety profile.
Macrolide and phenolic metabolites from the marine-derived fungus Paraconiothyrium sp. VK-13 with anti-inflammatory activity J. Antibiot. (IF 2.033) Pub Date : 2018-06-26 Tran Hong Quang, Dong Cheol Kim, Phan Van Kiem, Chau Van Minh, Nguyen Xuan Nhiem, Bui Huu Tai, Pham Hai Yen, Nguyen Thi Thanh Ngan, Hye Jin Kim, Hyuncheol Oh
Five new secondary metabolites, modiolides D-G (1−4) and 1-(2,5-dihydroxyphenyl)-3-methoxy-butan-1-one (8), one new natural product, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (7), along with three known compounds, modiolides A (5) and B (6), and 1-(2,5-dihydroxyphenyl)-2-buten-1-one (9) were isolated from a fermentation culture of the marine endophytic fungus Paraconiothyrium sp. VK-13. Their chemical structures were elucidated by the NMR and MS spectroscopic analysis as well as the modified Mosher’s method. Compounds 7 and 9 inhibited the overproduction of proinflammatory mediators NO and PGE2 in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 3.9 to 12.5 µM. The inhibitory effects of 7 and 9 on the release of NO and PGE2 were correlated with their significant suppression of iNOS and COX-2 protein expression, respectively. Furthermore, both compounds 7 and 9 inhibited the mRNA expression of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12, with IC50 values in a range of 2.4−12.5 µM.
Staurosporine: new lease of life for parent compound of today’s novel and highly successful anti-cancer drugs J. Antibiot. (IF 2.033) Pub Date : 2018-06-22 Satoshi Ōmura, Yukihiro Asami, Andy Crump
Staurosporine, together with such examples as penicillin, aspirin, ivermectin and sildenafil, exemplifies the role that serendipity has in drug discovery and why 'finding things without actually searching for them' retains a prominent role in drug discovery. Hitherto not clinically useful, due to its potency and promiscuity, new delivery technology is opening up new horizons for what was previously just the parent compound of innovative, highly-successful anti-cancer agents.
Biosynthetic studies on teleocidins in Streptomyces J. Antibiot. (IF 2.033) Pub Date : 2018-06-14 Ikuro Abe
Teleocidin B, with its unique indolactam-terpenoid scaffold, is a potent activator of protein kinase C. This short review summarizes our recent research progress on the biosynthesis of teleocidins in Streptomyces blastmyceticus NBRC 12747. We first identified the biosynthetic genes for teleocidin B, which include genes encoding a non-ribosomal peptide synthetase (tleA), a cytochrome P450 monooxygenase (tleB), an indol prenyltransferase (tleC), and a C-methyltransferase (tleD). Notably, the tleD gene is located outside the tleABC cluster. Our in vivo and in vitro analyses revealed that TleD not only catalyzes the C-methylation of the prenyl chain but also produces the indole-fused cyclic terpene structure. This is the first report of terpene cyclization initiated by the C-methylation of the prenyl double bond. In contrast, TleC catalyzes the geranylation of the C-7 position of the indole ring, in the reverse fashion. Our X-ray crystallographic analyses provided the structural basis for the reverse prenylation reactions, and structure-based mutagenesis successfully resulted in the production of unnatural, novel prenylated indolactams.
Prenylated indole alkaloids from co-culture of marine-derived fungi Aspergillus sulphureus and Isaria felina J. Antibiot. (IF 2.033) Pub Date : 2018-06-08 Shamil Sh. Afiyatullov, Olesya I. Zhuravleva, Alexandr S. Antonov, Dmitrii V. Berdyshev, Mikhail V. Pivkin, Vladimir A. Denisenko, Roman S. Popov, Andrey V. Gerasimenko, Gunhild von Amsberg, Sergey A. Dyshlovoy, Elena V. Leshchenko, Anton N. Yurchenko
Five new prenylated indole alkaloids, 17-hydroxynotoamide D (1), 17-O-ethylnotoamide M (2), 10-O-acetylsclerotiamide (3), 10-O-ethylsclerotiamide (4), and 10-O-ethylnotoamide R (5) were isolated from a co-culture of marine-derived fungi Aspergillus sulphureus KMM 4640 and Isaria felina KMM 4639. The structures of 1−5 were determined by detailed analysis of spectroscopic data and by comparison with related known compounds. The absolute configurations of 1−5 were determined by time-dependent density functional theory (TD-DFT) calculations of ECD spectra. Compound 2 is able to inhibit the colony formation of human prostate cancer cells 22Rv1 at non-cytotoxic concentration of 10 μM.
Instability of the 16S rRNA methyltransferase-encoding npmA gene: why have bacterial cells possessing npmA not spread despite their high and broad resistance to aminoglycosides? J. Antibiot. (IF 2.033) Pub Date : 2018-06-08 Yoshimasa Ishizaki, Yuko Shibuya, Chigusa Hayashi, Kunio Inoue, Teruo Kirikae, Tatsuya Tada, Tohru Miyoshi-Akiyama, Masayuki Igarashi
The NpmA bacterial 16S rRNA methyltransferase, which is identified from Escherichia coli strains, confers high resistance to many types of aminoglycoside upon its host cells. But despite its resistance-conferring ability, only two cases of its isolation from E. coli (14 years apart) have been reported to date. Here, we investigated the effect of the npmA gene on aminoglycoside resistance in Pseudomonas aeruginosa and Klebsiella pneumoniae and its stability in E. coli cells by comparing it with armA, another 16S rRNA methyltransferase gene currently spreading globally. As a result, we found that npmA conferred resistance to all types of aminoglycoside antibiotics we tested (except streptomycin) in both P. aeruginosa and K. pneumoniae, as well in E. coli. In addition, co-expression of armA and npmA resulted in an additive effect for the resistance. However, in return for the resistance, we also observed that the growth rates and the cell survivability of the strains transformed with the npmA-harboring plasmids were inferior than those of the control strains and that these plasmids were easily disrupted by IS10, IS1, and IS5 insertion sequences. We discuss these data in the context of the threat posed by pathogenic strains possessing npmA.
A call for doctors to recommend antibiotic-free foods: agricultural antibiotics and the public health crisis of antimicrobial resistance J. Antibiot. (IF 2.033) Pub Date : 2018-05-31 Martin A. Makary, Katerina Kaczmarski, Keeve Nachman
A call for doctors to recommend antibiotic-free foods: agricultural antibiotics and the public health crisis of antimicrobial resistance A call for doctors to recommend antibiotic-free foods: agricultural antibiotics and the public health crisis of antimicrobial resistance, Published online: 31 May 2018; doi:10.1038/s41429-018-0062-y A call for doctors to recommend antibiotic-free foods: agricultural antibiotics and the public health crisis of antimicrobial resistance
Activity of DNA-targeted C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates against aerobically and hypoxically grown Mycobacterium tuberculosis under acidic and neutral conditions J. Antibiot. (IF 2.033) Pub Date : 2018-05-24 Angelo Iacobino, Federico Giannoni, Lanfranco Fattorini, Federico Brucoli
Mycobacterium tuberculosis (Mtb) is the aetiological agent of tuberculosis, the leading cause of death worldwide from a single infectious agent. Mtb is a highly adaptable human pathogen that might enter a dormant non-replicating (NR), drug-tolerant stage. Reactivation of dormant Mtb can lead to active disease. Antibiotic treatments of active and latent tuberculosis are long, complex and may fail to fully eradicate the infection. Therefore, it is imperative to identify novel compounds with new mechanisms of action active against NR bacilli. Dormant Mtb habitat is mostly thought to be the pH-neutral and hypoxic caseous granuloma. We have used the Wayne culture model to reproduce this environment and tested the activities of two DNA-targeted agents, C8-linked-pyrrolobenzodiazepine(PBD)–polyamide conjugates 1 and 2, against Mtb grown in aerobic and hypoxic conditions in both acidic and pH-neutral media. PBD 2 showed growth inhibitory activity at 5.1 µg/ml against 19-day-old hypoxic NR Mtb cultures with 1.8 log10 CFU reduction on day 21 at pH 7.3. PBD 2 was particularly effective against 5-day-old aerobic cells at pH 7.3, with CFU reduction (>6.8 log10) on day 21 at 5.1 µg/ml being identical to that of rifampin at 8 µg/ml. PBD 2 qualifies as a promising lead against aerobic and NR Mtb.
Synthesis and insecticidal efficacy of pyripyropene derivatives focusing on the C-1, C-7, and C-11 positions’ substituent groups J. Antibiot. (IF 2.033) Pub Date : 2018-05-23 Kimihiko Goto, Ryo Horikoshi, Masaaki Mitomi, Kazuhiko Oyama, Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Ōmura
The C-1, C-7, and C-11 positions of pyripyropene A were chemically modified to improve the insecticidal activity. Some derivatives showed higher insecticidal activities against aphids than pyripyropene A. In particular, the derivative 5c, which possesses three cyclopropyl carbonyl groups at the C-1, C-7, and C-11 positions, had excellent insecticidal activity levels in field and laboratory trials.
Three new cyathane diterpenes with neurotrophic activity from the liquid cultures of Hericium erinaceus J. Antibiot. (IF 2.033) Pub Date : 2018-05-21 Yuting Zhang, Li Liu, Li Bao, Yanlong Yang, Ke Ma, Hongwei Liu
Three new cyathane diterpenes erinacines T–V (1–3), and two known cyathane diterpenes erinacine A (4) and erinacine P (5) were isolated from the liquid cultures of Hericium erinaceus. The structures of 1–3 were determined by extensive spectroscopic analysis. All isolated compounds were evaluated for the cytotoxicity, and neurite-promoting activities using PC12 cell line. Compounds 1–3, and 5 exhibited pronounced neurite outgrowth-promoting effects on PC12 cells in the range of 2.5−10 μM. Compound 4 showed weak cytotoxicity against PC12 cells with IC50 of 73.7 μM.
New antioxidants from the culture broth of Hericium coralloides J. Antibiot. (IF 2.033) Pub Date : 2018-05-17 Ji-Yul Kim, E-Eum Woo, In-Kyoung Lee, Bong-Sik Yun
In our effort to find antioxidants from the higher fungi, we isolated three new compounds (1–3) with a known compound, spirobenzofuran (4), from the culture broth of Hericium coralloides. Bioassay-guided fractionation led to the isolation of these compounds, and we determined the chemical structures through spectroscopic methods. These compounds exhibited antioxidant activity in the range of IC50 values of 29-66 μM in the 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging assay.
Paenialvin A–D, four peptide antibiotics produced by Paenibacillus alvei DSM 29 J. Antibiot. (IF 2.033) Pub Date : 2018-05-14 Jia Meng, Zheng Zhong, Pei-Yuan Qian
Four peptide antibiotics, named paenialvin A–D, were isolated from Paenibacillus alvei DSM 29. Mass spectrum analysis determined the molecular masses of paenialvin A–D to be 1891, 1875, 1877, and 1923 Da, respectively. Tandem mass spectra and nuclear magnetic resonance (NMR) were used to elucidate their chemical structures. Paenialvin A–D showed antimicrobial activity against most strains that were tested, including methicillin-resistant Staphalococcus aureus, Staphylococcus aureus, Bacillus subtilis, Loktanella hongkongensis, Escherichia coli, and Pseudomonas aeruginosa. In particular, the minimum inhibitory concentration of paenialvins against Staphalococcus aureus reached 0.8–3.2 μg/mL. Although they were cytotoxic against HeLa cells at a concentration of 50 μg/mL, the lack of hemolysis by paenialvins confirmed that they are potential candidates for anti-tumor drugs.
Bafilomycin C1 induces G0/G1 cell-cycle arrest and mitochondrial-mediated apoptosis in human hepatocellular cancer SMMC7721 cells J. Antibiot. (IF 2.033) Pub Date : 2018-05-11 Xiaoxiao Gao, Li Han, Nan Ding, Yu Mu, Peipei Guan, Caijuan Hu, Xueshi Huang
Bafilomycin C1, which was isolated from Streptomyces albolongus in our previous work, exhibited strong cytotoxicity against several cancer cell lines. This study aimed to evaluate its antitumor effect on human hepatocellular cancer SMMC7721 cells and the underlying mechanism in vitro and in vivo. MTT assay revealed that bafilomycin C1 retarded SMMC7721 cell growth and proliferation. Western blot and real-time qPCR analysis revealed that bafilomycin C1 caused partial G0/G1 phase cell-cycle arrest, downregulated the expression of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and upregulated the expression of p21. Moreover, bafilomycin C1 caused mitochondrial membrane dysfunction through oxidative stress. Furthermore, bafilomycin C1 decreased the expression of Bcl-2; increased the expression of Bax, p53, and P-p53; and increased cleavage of caspase-9 and caspase-3, thereby inducing the intrinsic caspase-dependent apoptotic pathway. In vivo experiments in mice suggested that bafilomycin C1 suppressed tumor growth with few side effects. Cell-cycle arrest and induced apoptosis in tumor tissues in a mouse model treated with bafilomycin C1 were demonstrated by histological analyses, western blot and TUNEL. These findings indicate that bafilomycin C1 may be a promising candidate for hepatic cellular cancer therapy.
Anti-Rhizopus activity of tanzawaic acids produced by the hot spring-derived fungus Penicillium sp. BF-0005 J. Antibiot. (IF 2.033) Pub Date : 2018-05-01 Takehiro Tominaga, Ryuji Uchida, Nobuhiro Koyama, Hiroshi Tomoda
A silkworm infection assay with the pathogenic fungus Rhizopus oryzae was established. Microbial culture broths were screened for anti-Rhizopus antibiotics using this assay. A new compound, tanzawaic acid R was isolated along with known and structurally related tanzawaic acids and arohynapene A from the culture broth of the hot spring-derived fungus Penicillium sp. BF-0005. The structure of tanzawaic acid R was elucidated by various spectroscopic data including 1D and 2D nuclear magnetic resonance spectroscopy. Tanzawaic acids A, B, C, and R and arohynapene A exhibited antifungal activity against R. oryzae. Tanzawaic acids A and B dose-dependently exerted therapeutic effects in the silkworm infection assay with R. oryzae.
Antibacterial anthraquinone derivatives isolated from a mangrove-derived endophytic fungus Aspergillus nidulans by ethanol stress strategy J. Antibiot. (IF 2.033) Pub Date : 2018-05-01 Sui-Qun Yang, Xiao-Ming Li, Gang-Ming Xu, Xin Li, Chun-Yan An, Bin-Gui Wang
Three new natural products, including a new anthraquinone derivative isoversicolorin C (1), a new xanthone analog isosecosterigmatocystin (2), and a new amino acid derivative, glulisine A (3), along with six related metabolites (4–9) were isolated from the culture broth and mycelia extracts of the mangrove-derived endophytic fungus Aspergillus nidulans MA-143 under 0.1% ethanol stress. Their structures were elucidated by detailed analysis of their NMR spectra, ECD spectrum, and X-ray crystallographic experiments. Compounds 1 and 4 showed potent antibacterial activity against some of the tested microbes.
Cyclo(Pro-DOPA), a third identified bioactive metabolite produced by Streptomyces sp. 8812 J. Antibiot. (IF 2.033) Pub Date : 2018-04-26 Jolanta Solecka, Aleksandra Rajnisz-Mateusiak, Adam Guspiel, Katarzyna Jakubiec-Krzesniak, Joanna Ziemska, Robert Kawęcki, Dorota Kaczorek, Dorota Gudanis, Joanna Jarosz, Joanna Wietrzyk
A new metabolite, cyclic dipeptide, cis-(3S,8aS)-3-(3,4-dihydroxybenzyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, named JS-3 was isolated from Streptomyces sp. 8812 fermentation broth. Its chemical structure was established by means of spectroscopic analysis. A wide-range-screening study, which included inhibition assay of dd-carboxypeptidase/transpeptidase activity, determination of antibacterial, antifungal, and antiproliferative activities as well as free-radical scavenging was performed. To authors knowledge, this is the first isolation of such compound from natural sources and the first one from bacteria, Streptomyces.
Isolation of a jadomycin incorporating l-ornithine, analysis of antimicrobial activity and jadomycin reactive oxygen species (ROS) generation in MDA-MB-231 breast cancer cells J. Antibiot. (IF 2.033) Pub Date : 2018-04-26 Stephanie M. Forget, Andrew W. Robertson, Steven R. Hall, Jeanna M. MacLeod, David P. Overy, Russell G. Kerr, Kerry B. Goralski, David L. Jakeman
Herein, we report the characterization and antimicrobial activity of a previously unreported jadomycin (1) obtained from a culture of S. venezuelae ISP5230 with l-ornithine (Orn). 1 arises from the rearrangement of a putative five-membered ring containing jadomycin incorporating Orn, whereby intramolecular attack of the E-ring carbonyl from the δ-NH2 group of the Orn side chain results in collapse of the oxazolone ring and formation of a stable six-membered lactam. This rearrangement produces a jadomycin with a 3a hemiaminal position that is susceptible to solvolysis. A structure–activity relationship is discussed based on the antimicrobial activity of 1 compared to previously reported jadomycins, providing evidence that the presence of a 3a hemiaminal enhances activity against Gram-positive bacteria. Additionally, assays to quantify reactive oxygen species (ROS) generation and cell viability were performed using a series of nine jadomycins. Compound 1 was found to produce the highest ROS activity and to possess the greatest cytotoxicity against MDA-MB-231 breast cancer cells.
Anti-inflammatory phomalichenones from an endolichenic fungus Phoma sp. J. Antibiot. (IF 2.033) Pub Date : 2018-04-26 Jong Won Kim, Wonmin Ko, Eun Kim, Gil Soo Kim, Gwi Ja Hwang, Sangkeun Son, Min-Hye Jeong, Jae-Seoun Hur, Hyuncheol Oh, Sung-Kyun Ko, Jae-Hyuk Jang, Jong Seog Ahn
Four new compounds, phomalichenones A–D (1–4), and seven known compounds (5–11) were isolated from the cultures of an endolichenic fungus Phoma sp. EL002650. Their structures were determined by the analysis of their spectroscopic data (NMR and MS). Compounds 1 and 6 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In addition, compound 1 diminished the protein expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and decreased the mRNA expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin(IL)-1β, and IL-6.
Hamuramicins A and B, 22-membered macrolides, produced by an endophytic actinomycete Allostreptomyces sp. K12-0794 J. Antibiot. (IF 2.033) Pub Date : 2018-04-24 Takuya Suga, Tōru Kimura, Yuki Inahashi, Masato Iwatsuki, Kenichi Nonaka, Akira Také, Atsuko Matsumoto, Yōko Takahashi, Satoshi Ōmura, Takuji Nakashima
Two new compounds, designated as hamuramicins A (1) and B (2), were isolated from the cultured broth of an endophytic actinomycete Allostreptomyces sp. K12-0794 by silica gel column chromatography and HPLC. The structures of 1 and 2 were elucidated as 22-membered macrolide containing triene and trienone with an alkyl side chain by spectroscopic analyses including NMR experiments. Both compounds showed growth inhibition activity against Kocuria rhizophia and Xanthomonas oryzae pv. oryzae as well as human cell line toxicity.
The activities of wortmannilactones against helminth electron transport chain enzymes, structure-activity relationships, and the effect on Trichinella spiralis infected mice J. Antibiot. (IF 2.033) Pub Date : 2018-04-24 Wen-Cai Liu, Yi-Xin Ren, Ai-Yu Hao, Sun Yu, Xuan Shi, Xue-Qiang Zhang, Yan Xing, Zhi-Long Xiu, Yu Cui, Yue-Sheng Dong
Biotransformation of wortmannilactone F (3) using the marine-derived fungus DL1103 generated wortmannilactone M (1), a novel analog of wortmannilactone, which was a reduction product of 3 at the C-3 carbonyl group. The in vitro inhibitory activities of 10 wortmannilactones, including 1, against electron transport enzymes indicated that all the wortmannilactones were selective inhibitors of NADH-fumarate reductase and NADH–rhodoquinone reductase. The structure–activity relationship analysis showed that the relative configuration of C1” and C5”, the positions of double bonds, the oxygen atoms in the dihydropyran moiety, and the keto-carbonyl group in the oxabicyclo-[2.2.1]-heptane moiety were important to the inhibitory activity of wortmannilactones. In vivo studies indicated that 3 significantly decreased the number and size of adult worms in Trichinella spiralis-infected mice in a dose-dependent manner. Notable changes in the cuticle and microvilli of T. spiralis were also observed. Our data provided useful information in the research and development of polyketides with dihydropyran and oxabicyclo [2.2.1] heptane moieties as antihelminthics.
Quellenin, a new anti-Saprolegnia compound isolated from the deep-sea fungus, Aspergillus sp. YK-76 J. Antibiot. (IF 2.033) Pub Date : 2018-04-23 Konami Takahashi, Kazunari Sakai, Wataru Fukasawa, Yuriko Nagano, Sakiko Orui Sakaguchi, Andre O. Lima, Vivian H. Pellizari, Masato Iwatsuki, Kiyotaka Takishita, Takao Yoshida, Kenichi Nonaka, Katsunori Fujikura, Satoshi Ōmura
Saprolegnia parasitica, belonging to oomycetes, is one of virulent pathogen of fishes such as salmon and trout, and causes tremendous damage and losses in commercial aquacultures by saprolegniasis. Previously, malachite green, an effective medicine, had been used to control saprolegniasis. However, this drug has been banned around the world due to its mutagenicity. Therefore, novel anti-saprolegniasis compounds are urgently needed. As a new frontier to discover bioactive compounds, we focused on the deep-sea fungi for the isolation of anti-saprolegniasis compounds. In this paper, on the course of anti-saprolegniasis agents from 546 cultured broths of 91 deep-sea fungal strains, we report a new compound, named quellenin (1) together with three known compounds, diorcinol (2), violaceol-I (3) and violaceol-II (4), from deep-sea fungus Aspergillus sp. YK-76. This strain was isolated from an Osedax sp. annelid, commonly called bone-eating worm, collected at the São Paulo Ridge in off Brazil. Compounds 2, 3 and 4 showed anti-S. parasitica activity. Our results suggest that diorcinol and violaceol analogs and could be good lead candidates for the development of novel agents to prevent saprolegniasis.
Effect of antimicrobial peptides from Galleria mellonella on molecular models of Leishmania membrane. Thermotropic and fluorescence anisotropy study J. Antibiot. (IF 2.033) Pub Date : 2018-04-20 Isabel Andrea Patiño-Márquez, Marcela Manrique-Moreno, Edwin Patiño-González, Małgorzata Jemioła-Rzemińska, Kazimierz Strzałka
Antimicrobial peptides are molecules of natural origin, produced by organisms such as insects, which have focused attention as potential antiparasitic agents. They can cause the death of parasites such Leishmania by interacting with their membrane. In this study, additional information was obtained on how the anionic peptide 2 and cecropin D-like peptide derived from Galleria mellonella interact with liposomes that mimic the composition of the Leishmania membrane. In order to do this, lipid bilayers consisting of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine, and dimyristoylphosphatidylglycerol were constructed. The effect of the peptides on these membranes was evaluated using calorimetry analysis and fluorescence spectroscopy. The results obtained using differential scanning calorimetry indicated a concentration-dependent effect on membranes composed of phosphatidylserine and phosphatidylglycerol, showing a preference of both peptides for anionic lipids. The binding of the peptides drastically reduced the transition enthalpy in the phosphatidylserine and phosphatidylglycerol liposomes. The results suggest that the mode of action of anionic peptide 2 and cecropin D-like peptide is different, with a higher effect of cecropin D-like on the anionic lipids, which led to changes in the main transition temperature and a complete solubilization of the vesicles. Interactions between peptides and phosphatidylcholine, which is the most abundant lipid on the surface of Leishmania cells, were evaluated using isothermal titration calorimetry and the anisotropy of fluorescence of DPH. The peptides had a slight effect on the gel phase of the phosphatidylcholine, with changes in the anisotropy correlated with that observed by DSC. The results showed a selectivity of these peptides toward some lipids, which will direct the study of the development of new drugs.
Identification and heterologous expression of the actinoallolide biosynthetic gene cluster J. Antibiot. (IF 2.033) Pub Date : 2018-04-20 Yuki Inahashi, Taro Shiraishi, Akira Také, Atsuko Matsumoto, Yōko Takahashi, Satoshi Ōmura, Tomohisa Kuzuyama, Takuji Nakashima
Actinoallolides are anti-trypanosomal macrolides isolated from the secondary metabolites of two endophytic actinomycete strains, Actinoallomurus fulvus MK10-036 and K09-0307. A putative actinoallolide biosynthetic gene cluster was predicted from the genome sequence of the strain K09-0307. The gene cluster spans a contiguous 53 kb DNA region that comprises seven genes encoding three PKSs (aalA1, aalA2, and aalA3), cytochrome P450 (aalB), acyl-CoA dehydrogenase (aalC), crotonyl-CoA reductase (aalD), and TetR family regulator (aalR). The entire gene cluster was cloned into a plasmid pYIK1 by assembling DNA fragments, which were obtained from two cosmids containing left and right parts of the gene cluster. Following the introduction of an ermE* promoter at 100bp upstream from the start codon of aalA1, the gene cluster was introduced into Streptomyces coelicolor M1152. Subsequent LC-MS analysis revealed production of actinoallolide A in the culture broth. Thus, the actinoallolide biosynthetic gene cluster was identified by heterologous expression in Streptomyces.
A new protein tyrosine phosphatase 1B inhibitory α-pyrone-type polyketide from Okinawan plant-associated Aspergillus sp. TMPU1623 J. Antibiot. (IF 2.033) Pub Date : 2018-04-20 Hiroyuki Yamazaki, Kenta Takahashi, Natsuki Iwakura, Tatsuki Abe, Masanari Akaishi, Satomi Chiba, Michio Namikoshi, Ryuji Uchida
A new polyenyl-α-pyrone polyketide, aspopyrone A (1), was isolated from a culture broth of Okinawan plant-associated Aspergillus sp. TMPU1623 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was assigned based on NMR experiments. Compound 1 exhibited protein tyrosine phosphatase (PTP) 1B and T-cell PTP (TCPTP) inhibitory activities with IC50 values of 6.7 and 6.0 μM, respectively.
Cationic amphiphilic bolaamphiphile-based delivery of antisense oligonucleotides provides a potentially microbiome sparing treatment for C. difficile J. Antibiot. (IF 2.033) Pub Date : 2018-04-19 Arun K. Sharma, Jacek Krzeminski, Volkmar Weissig, John P. Hegarty, David B. Stewart
Conventional antibiotics for C. difficile infection (CDI) have mechanisms of action without organismal specificity, potentially perpetuating the dysbiosis contributing to CDI, making antisense approaches an attractive alternative. Here, three (APDE-8, CODE-9, and CYDE-21) novel cationic amphiphilic bolaamphiphiles (CABs) were synthesized and tested for their ability to form nano-sized vesicles or vesicle-like aggregates (CABVs), which were characterized based on their physiochemical properties, their antibacterial activities, and their toxicity toward colonocyte (Caco-2) cell cultures. The antibacterial activity of empty CABVs was tested against cultures of E. coli, B. fragilis, and E. faecalis, and against C. difficile by “loading” CABVs with 25-mer antisense oligonucleotides (ASO) targeting dnaE. Our results demonstrate that empty CABVs have minimal colonocyte toxicity until concentrations of 71 µM, with CODE-9 demonstrating the least toxicity. Empty CABVs had little effect on C. difficile growth in culture (MIC90 ≥ 160 µM). While APDE-8 and CODE-9 nanocomplexes demonstrated high MIC90 against C. difficile cultures (>300 µM), CYDE-21 nanocomplexes demonstrated MIC90 at CABV concentrations of 19 µM. Empty CABVs formed from APDE-8 and CODE-9 had virtually no effect on E. coli, B. fragilis, and E. faecalis across all tested concentrations, while empty CYDE-21 demonstrated MIC90 of >160 µM against E. coli and >40 µM against B. fragilisand E. faecalis. Empty CABVs have limited antibacterial activity and they can deliver an amount of ASO effective against C. difficile at CABV concentrations associated with limited colonocyte toxicity, while sparing other bacteria. With further refinement, antisense therapies for CDI may become a viable alternative to conventional antibiotic treatment.
Design, synthesis, biological activity and structure-activity relationship studies of chalcone derivatives as potential anti-Candida agents J. Antibiot. (IF 2.033) Pub Date : 2018-04-19 Jéssica T. Andrade, Felipe R. S. Santos, William G. Lima, Carla D. F. Sousa, Lohanna S. F. M. Oliveira, Rosy I. M. A. Ribeiro, Ana J. P. S. Gomes, Marcelo G. F. Araújo, José A. F. P. Villar, Jaqueline M. S. Ferreira
Vulvovaginal candidiasis (VVC) affects millions of women around the world every year. Candida albicans is the most frequently isolated pathogen in women and its rapid ability to develop resistance to first and second line therapies has boosted the search for new and effective antifungal agents. In this study, we show the in vitro anti-Candida activity of fifteen synthetic chalcone analogs and their antifungal potential in an in vivo model of VVC. Chalcone 12 showed potent antifungal effects, being able to inhibit the growth of Candida spp. at a concentration of 15.6 µg mL−1. In addition, mechanism of action studies have indicated the ergosterol fungal membrane as the target of this compound. Despite a considerable antifungal activity, the chalcone 12 showed high cytotoxicity in kidney cells lineages. Moreover, this compound was able to reduce Candida-associated virulence, impairing yeast–hyphal transition in C. albicans. An in vivo model of VVC showed that chalcone 12 significantly reduces the fungal load. Taken together, these findings showed that the chalcone 12 is a potent anti-Candida agent in vitro beyond of contribute to improve the fungal infection in a model of CVV. However, it showed low selectivity and high toxicity, suggesting molecular modifications to minimize these proprieties.
Two new spliceostatin analogs from the strain Pseudomonas sp. HS-NF-1408 J. Antibiot. (IF 2.033) Pub Date : 2018-04-17 Yue Zhao, Junwei Zhao, Chang Lu, Hui Zhang, Huan Qi, Shanwen Jiang, Xiaowei Guo, Jidong Wang, Wensheng Xiang
Two new spliceostatin derivatives, designed as spliceostatin H (1) and spliceostatin I (2), and one known compound FR901464 (3), were isolated from the strain Pseudomonas sp. HS-NF-1408. Their structures were determined by the comprehensive spectroscopic data, including 1D, 2D NMR, MS spectral analysis and comparison with data from the literature. Compound 1 exhibited potent cytotoxicity activity against A549 and HepG2 with IC50 values of 3.57 and 16.72 μg/ml, respectively.
Polyketides from two Chaetomium species and their biological functions J. Antibiot. (IF 2.033) Pub Date : 2018-04-16 He Li, Zhong-Bin Liao, Dan Tang, Wen-Bo Han, Qiang Zhang, Jin-Ming Gao
Four new secondary metabolites, chaetosemins G-J (1−4), along with 11 known ones (5−15) were isolated from the culture of C. seminudum C208 and Chaetomium sp. C521. Their structures were determined by extensive NMR spectroscopic analyses. These metabolites were evaluated in vitro for antifungal, antioxidant, toxicity, and α-glucosidase inhibitory activities. Chaetosemin J (4) and monaschromone (5) significantly inhibited the growth of four plant pathogenic fungi Botrytis cinerea, Alternaria solani, Magnaporthe oryzae, and Gibberella saubinettii with the minimum inhibitory concentrations (MIC) values ranging from 6.25 to 25.0 μM. Moreover, both epicoccone B (11) and flavipin (14) exhibited the DPPH free radical scavenging ability with IC50 values of 10.8 and 7.2 μM, respectively, and had more potent α-glucosidase inhibition than the drug acarbose with IC50 values of 27.3 and 33.8 μM, respectively. Monaschromone (5) might act as the lead compound of pesticide.
Glycosylated piericidins from an endophytic streptomyces with cytotoxicity and antimicrobial activity J. Antibiot. (IF 2.033) Pub Date : 2018-04-12 Ning-Ning Shang, Zhouxin Zhang, Jian-Ping Huang, Li Wang, Jianying Luo, Jing Yang, Teng Peng, Yijun Yan, Ya-Tuan Ma, Sheng-Xiong Huang
Two new glycosylated piericidins, glucopiericidinol A3 (1) and 7-demethyl-glucopiericidin A (2), along with four known analogs were isolated from the culture broth of Streptomyces sp. KIB-H1083. The chemical structures of new compounds were elucidated by spectroscopic analyses. Their cytotoxicity on HL-60, SMMC-772, A-549, MCF-7, and SW480 cell lines, as well as antimicrobial activities was evaluated. The results showed that glucopiericidin A (4) has potent cytotoxicity against HL-60, SMMC-772, A-549, and MCF-7 cell lines with IC50 values of 0.34, 0.65, 0.60, and 0.50 μm, respectively. For the antimicrobial activity, piericidin A (6) showed most powerful inhibitory activities against Xanthomonas oryzae pv. oryzicola, and Penicillium decumbens.
Reclassification of Nocardia species based on whole genome sequence and associated phenotypic data J. Antibiot. (IF 2.033) Pub Date : 2018-04-04 Tomohiko Tamura, Shoko Ohji, Natsuko Ichikawa, Akira Hosoyama, Atsushi Yamazoe, Moriyuki Hamada, Hisayuki Komaki, Chiyo Shibata, Tetsuhiro Matsuzawa, Tohru Gonoi, Ken-ichiro Suzuki, Nobuyuki Fujita
Type strains of 72 validated Nocardia species were phylogenetically analyzed based on the multilocus sequence analysis (MLSA) concatenated atpD–groL1–groL2–recA–rpoA–secY–sodA–ychF. Furthermore, their similarity based on digital DNA–DNA hybridization (dDDH) was calculated. Nocardia soli, Nocardia cummidelens and Nocardia salmonicida, Nocardia nova and Nocardia elegans, Nocardia exalbida and Nocardia gamkensis, and Nocardia coubleae and Nocardia ignorata formed coherent clades, respectively. Moreover, each set showed over 70% relatedness by dDDH and shared common phenotypic characteristics. Therefore, we propose a reclassification of Nocardia soli and Nocardia cummidelens as a later heterotypic synonym of Nocardia salmonicida, Nocardia elegans as a later heterotypic synonym of Nocardia nova, Nocardia gamkensis as a later heterotypic synonym of Nocardia exalbida, and Nocardia coubleae as a later heterotypic synonym of Nocardia ignorata.
Roquefortine J, a novel roquefortine alkaloid, from the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475 J. Antibiot. (IF 2.033) Pub Date : 2018-04-04 Siwen Niu, Ning Wang, Chun-Lan Xie, Zuowang Fan, Zhuhua Luo, Hai-Feng Chen, Xian-Wen Yang
Chemical investigation on the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475 led to the isolation of a previously undescribed (roquefortine J, 1) and four known (2−5) roquefortine alkaloids, along with six ergosterol analogues (6−11). The planar structure of 1 was established mainly on the basis of extensive analysis of its 1D, 2D NMR, and HRESIMS spectra. The absolute configuration of 1 was determined by comparison of the calculated and experimental electronic circular dichroism spectra. Compounds 5, 6, and 7 exhibited potent anti-proliferative effects against HepG2 tumor cells with IC50 values of 7.0, 8.6, and 8.2 μM, respectively.
Correction to: Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria J. Antibiot. (IF 2.033) Pub Date : 2018-03-27 Fumiaki Nakamura, Norio Kudo, Yuki Tomachi, Akiko Nakata, Misao Takemoto, Akihiro Ito, Hodaka Tabei, Daisuke Arai, Nicole de Voogd, Minoru Yoshida, Yoichi Nakao, Nobuhiro Fusetani
Correction to: Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria Correction to: Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria, Published online: 27 March 2018; doi:10.1038/s41429-017-0019-6 Correction to: Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria
Tolyprolinol, a new dipeptide from Tolypocladium sp. FKI-7981 J. Antibiot. (IF 2.033) Pub Date : 2018-03-22 Wataru Fukasawa, Natsuki Mori, Masato Iwatsuki, Rei Hokari, Aki Ishiyama, Moe Nakajima, Takahito Ouchi, Kenichi Nonaka, Hiroki Kojima, Hirotaka Matsuo, Satoshi Ōmura, Kazuro Shiomi
A new dipeptide, named tolyprolinol, was isolated from the static culture of a fungus, Tolypocladium sp. FKI-7981. The structure of tolyprolinol was elucidated as N-acetyl-l-phenylalanyl-l-prolinol. It showed moderate antimalarial activity but did not show cytotoxicity or any other antimicrobial property.
Cystargamide B, a cyclic lipodepsipeptide with protease inhibitory activity from Streptomyces sp. J. Antibiot. (IF 2.033) Pub Date : 2018-03-22 Shigeru Kitani, Mitsuki Yoshida, Ousana Boonlucksanawong, Watanalai Panbangred, Atchareeya Anuegoonpipat, Takeshi Kurosu, Kazuyoshi Ikuta, Yasuhiro Igarashi, Takuya Nihira
We identified a new cyclic lipodepsipeptide, cystargamide B (1), from the mycelial extract of a Kaempferia galanga rhizome-derived actinomycete strain, Streptomyces sp. PB013. The planar structure was elucidated based on high resolution fast-atom bombardment mass spectrometry (HRFABMS) spectroscopy and one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic data. The absolute configurations of the constituent amino acids were determined using advanced Marfey’s method. Cystargamide B (1) includes rare structural units: a 5-hydroxytryptophan residue and a 2,3-epoxy fatty acid side chain. Notably, cystargamide B (1) inhibited the protease activity of the NS2B/NS3 complex from dengue virus.
Confirmation of the absolute configuration of Stachybotrin C using single-crystal X-ray diffraction analysis of its 4-bromobenzyl ether derivative J. Antibiot. (IF 2.033) Pub Date : 2018-03-19 Yu Kuroda, Keiko Hasegawa, Keiichi Noguchi, Kazuhiro Chiba, Keiji Hasumi, Yoshikazu Kitano
The absolute configuration of Stachybotrin C was confirmed in this study. After synthesizing the dimethyl ethers of Stachybotrin C, the C-8 epimer was analyzed by 1D NOESY. However, the stereochemistry determination was difficult through the NOE correlations. Instead, the di(4-bromobenzyl) ether of Stachybotrin C was derived and used for X-ray diffraction analysis, because its single crystal was easier to obtain than that of the original Stachybotrin C. The stereochemistry of Stachybotrin C was determined to be (8S, 9R). This derivatization approach may also be used to prepare single crystals of the analogues.
Spiciferone analogs from an endophytic fungus Phoma betae collected from desert plants in West China J. Antibiot. (IF 2.033) Pub Date : 2018-03-14 Xiang-Mei Tan, Lu-Ying Li, Li-Yan Sun, Bing-Da Sun, Shu-Bin Niu, Meng-Hua Wang, Xiao-Yan Zhang, Wen-Song Sun, Gui-Shan Zhang, Hui Deng, Xiao-Ke Xing, Zhong-Mei Zou, Gang Ding
Endophytic fungi from desert, arid, and grassland areas are an ecologically important but unique group with poor chemical investigation. During our ongoing study to mine bioactive secondary metabolites from unique fungal environments, a new shunt product spiciferone F (1) including two new analogs spiciferones G (2) and H (3) together with four known ones spiciferone A (4), spiciferol A (5), 6, and 7 were isolated from endophytic fungus Phoma betae inhabiting in plant Kalidium foliatum (Pall.) Moq from Ningxia Province of West China. The planar, relative, and absolute configurations of these new compounds were elucidated by nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, and electronic circular dichroism experiments. According to the shunt products, intermediates and analogs isolated from this endophytic fungus, the possible biosynthetic pathway of spiciferones was reconstructed. Compounds 1–7 were evaluated cytotoxic activities against three cancer cell lines HCT 116, HeLa, and MCF7, and only did 1 display strong biological effect against MCF7 with a half-maximal inhibitory concentration value at 7.73 ± 0.11 μM compared with the cis-platinum (14.32 ± 1.01 μM).
Umezawamides, new bioactive polycyclic tetramate macrolactams isolated from a combined-culture of Umezawaea sp. and mycolic acid-containing bacterium J. Antibiot. (IF 2.033) Pub Date : 2018-03-14 Shotaro Hoshino, Chin Piow Wong, Masahiro Ozeki, Huiping Zhang, Fumiaki Hayashi, Takayoshi Awakawa, Shumpei Asamizu, Hiroyasu Onaka, Ikuro Abe
New polycyclic tetramate macrolactams, Umezawamides A (1) and B (2) were isolated from a combined-culture of Umezawaea sp. RD066910 and mycolic-acid containing bacterium Tsukamurella pulmonis TP-B0596. Their planar structures and partial stereochemistries were determined based on the spectroscopic analysis, MMFF conformational search, and ECD calculations. Umezawamides are the first secondary metabolites isolated from the genus Umezawaea and they exhibited cytotoxicities to P388 murine leukemia cells. Furthermore, umezawamide A (1) showed growth inhibitory activity against Candida albicans.
Streptosporangium minutum sp. nov., isolated from garden soil exposed to microwave radiation J. Antibiot. (IF 2.033) Pub Date : 2018-03-07 Marilize Le Roes-Hill, Kim Durrell, Alaric Prins, Paul R. Meyers
The actinobacterium, strain M26T, was isolated from garden soil that was pre-treated with microwave radiation. The soil sample was collected in Roodepoort, Gauteng Province, South Africa as part of an antibiotic-screening programme. The isolate produced branched vegetative mycelium with sporangiophores bearing small sporangia ranging from 3 to 6 μm in diameter. Rapid genus identification revealed that the isolate belongs to the genus Streptosporangium. To confirm this result, the strain was subjected to polyphasic taxonomic characterisation. Chemotaxonomic characteristics were as follows: meso-DAP in the peptidoglycan, the whole-cell hydrolysate yielded madurose, predominant menaquinones were MK9 (21%), MK9(H2) (40%), MK9(H4) (31%) and MK9(H6) (3%); the polar lipid profile included an aminolipid, phosphoglycolipids, phosphatidylethanolamine, and phosphatidylmonomethylethanolamine. In addition, the fatty acid profile showed the presence of C16:0 (12.8%), C17:1ω8c (14.2%), and 10-methyl-C17:0 (15.8%). Furthermore, 16S rRNA gene sequence phylogenetic analysis showed that the strain is closely related to members of the genus Streptosporangium, which supports its classification within the family Streptosporangiaceae. Strain M26T exhibited antibiosis against a range of pathogenic bacteria, including, but not limited to Acinetobacter baumannii ATCC 19606T, Enterobacter cloacae subsp. cloacae ATCC BAA-1143, Enterococcus faecalis ATCC 51299 (vancomycin resistant), Escherichia coli ATCC 25922, Listeria monocytogenes ATCC 19111, Mycobacterium tuberculosis H37RvT, Pseudomonas aeruginosa ATCC 27853, Salmonella enterica subsp. arizonae ATCC 13314T, and the methicillin-resistant Staphylococcus aureus subsp. aureus ATCC 33591 (MRSA). The name Streptosporangium minutum is proposed with the type strain M26T (=LMG 28850T =NRRL B-65295T).
Structure and biosynthesis of mayamycin B, a new polyketide with antibacterial activity from Streptomyces sp. 120454 J. Antibiot. (IF 2.033) Pub Date : 2018-03-07 Sheng Tao Bo, Zi Fei Xu, Li Yang, Ping Cheng, Ren Xiang Tan, Rui Hua Jiao, Hui Ming Ge
Mayamycin B, a new antibacterial type II polyketide, together with its known congener mayamycin A, were isolated from Streptomyces sp. 120454. The structure of new compound was elucidated by extensive spectroscopic analysis and comparison with literature data. Sequencing and bioinformatics analysis revealed the biosynthetic gene cluster for mayamycins A and B.
Computational study on formation of 15-membered azalactone by double reductive amination using molecular mechanics and density functional theory calculations J. Antibiot. (IF 2.033) Pub Date : 2018-03-07 Hiroaki Gouda, Naofumi Nakayama, Tomoaki Miura, Kenichi Kanemoto, Keiichi Ajito
Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 Å, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization.
Pyrizomicin A and B: structure and bioactivity of new thiazolyl pyridines from Lechevalieria aerocolonigenes K10-0216 J. Antibiot. (IF 2.033) Pub Date : 2018-03-07 Tōru Kimura, Yuki Inahashi, Hirotaka Matsuo, Takuya Suga, Masato Iwatsuki, Kazuro Shiomi, Yōko Takahashi, Satoshi Ōmura, Takuji Nakashima
Two new antibiotics, designated pyrizomicin A and B, were isolated from the cultured broth of a rare actinomycete strain, Lechevalieria aerocolonigenes K10-0216, by silica gel and HPLC purification. The chemical structures of pyrizomicin A and B were elucidated as new thiazolyl pyridine compounds by nuclear magnetic resonance and mass spectrometry. Pyrizomicin A and B both showed antimicrobial activity.
The chejuenolide biosynthetic gene cluster harboring an iterative trans-AT PKS system in Hahella chejuensis strain MB-1084 J. Antibiot. (IF 2.033) Pub Date : 2018-02-26 Bee Gek Ng, Jae Woo Han, Dong Wan Lee, Gyung Ja Choi, Beom Seok Kim
Hahella chejuensis MB-1084 is a Gram-negative marine bacterial strain that produces unusual 17-membered carbocyclic tetraenes, chejuenolide A and B. Two fosmid clones responsible for chejuenolide production were identified from the genomic DNA library of the MB-1084 strain. Systematic inactivation of the open reading frames (ORFs) in the sequenced region defines the boundaries of the chejuenolide (che) biosynthetic gene cluster (24.9 kbp) that encodes one non-ribosomal peptide synthase (NRPS)-polyketide synthase (PKS) hybrid protein, three modular PKSs, two PKS domains, and an amine oxidase homolog. Based on the results, we found that the che PKSs have non-canonical features such as trans-AT system and insufficient number of KS domains (five KS domains) for chejuenolide production (requires eight rounds of Claisen condensation reaction). Heterologous expression of the che PKSs in the E. coli BAP1 strain provides strong evidence of the iterative characteristic of the modular PKSs. Additionally, the phylogenetic relatedness of the KS domains of che PKSs and other trans-AT PKSs was analyzed to propose a possible pathway for chejuenolide biosynthesis.
Planctopirus hydrillae sp. nov., an antibiotic producing Planctomycete isolated from the aquatic plant Hydrilla and its whole genome shotgun sequence analysis J. Antibiot. (IF 2.033) Pub Date : 2018-02-21 Subhash Yadav, Radha Vaddavalli, Srinivas Siripuram, Ramaprasad Veera Venkata Eedara, Shivani Yadav, Ojha Rabishankar, Tushar Lodha, Sasikala Chintalapati, VenkataRamana Chintalapati
An antibiotic producing novel Planctomycete strain, designated JC280T, was isolated from the surface of the plant Hydrilla verticillata collected from an alkaline lake (Buffalo lake), University of Hyderabad, Hyderabad, India. The morphological and chemotaxonomic properties of strain JC280T were in agreement with the characteristics of the genus Planctopirus. The cell shape was spherical to ovoid and some were tear drop shaped. The cells were Gram-stain-negative divided by budding presenting stalks and rosette formation and were non-sporulating. Crateriform structures with a sub-polar flagellum were observed. Characteristic polyamines were putrescine and spermidine. Diagnostic polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, an unidentified phospholipid (PL1), unidentified glycolipids (GL1-2), an unidentified aminophospholipid (APL), and an unidentified lipid (L3). Major (>10%) fatty acids were C16:0, C17:1ω8c, C18:1ω9c, and summed feature-3. Major (88%) respiratory quinone was MK-6 with minor amount (12%) of MK-7. Strain JC280T showed 99.7% 16S rRNA gene sequence similarity with Planctopirus limnophila DSM 3776T. To resolve their full taxonomic position, the genome sequence was obtained and compared with the available P. limnophila DSM 3776T genome. The genome sequence of strain JC280T was 5,750,243 bp in size with a total of 4490 protein-coding genes, 66 RNA genes, and 2 CRISPR repeats. Based on whole-genome statistics, ANI value, in silico DDH, diversity of secondary metabolite biosynthetic gene clusters, distinct physiological, biochemical and chemotaxonomic differences, strain JC280T represents a new species in the genus Planctopirus, for which the name Planctopirus hydrillae sp. nov. is proposed. The type strain is JC280T (=KCTC 42880T = LMG 29153T).
Fluvirucin B6, a new macrolactam isolated from a marine-derived actinomycete of the genus Nocardiopsis J. Antibiot. (IF 2.033) Pub Date : 2018-02-21 Alain S. Leutou, Inho Yang, Tu Cam Le, Dongyup Hahn, Kyung-Min Lim, Sang-Jip Nam, William Fenical
A new 14-membered macrolactam natural product, fluvirucin B6 (1), was isolated from a marine-derived actinomycete, Nocardiopsis sp. CNQ-115, via HPLC-UV guided isolation. The chemical structure of 1 was elucidated by 1D and 2D NMR spectroscopic data analysis. Compound 1 showed a weak activity against Gram-positive bacteria, whereas it was inactive against Gram-negative bacteria.
Furanoaustinol and 7-acetoxydehydroaustinol: new meroterpenoids from a marine-derived fungal strain Penicillium sp. SF-5497 J. Antibiot. (IF 2.033) Pub Date : 2018-02-20 Jin-Soo Park, Tran Hong Quang, Chi-Su Yoon, Hye Jin Kim, Jae Hak Sohn, Hyuncheol Oh
Two new meroterpenoid-type fungal metabolites, furanoaustinol (1) and 7-acetoxydehydroaustinol (2), were isolated from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, along with eight (3–10) known meroterpenoids. Their structures were elucidated mainly based on the analysis of their NMR (1D and 2D) and MS data. Particularly, the novel meroterpenoid, furanoaustinol (1), belonging to the austin group, was identified to possess an unprecedented hexacyclic ring system. Biological evaluation of these compounds revealed that furanoaustinol (1) weakly inhibited the activity of protein tyrosine phosphatase 1B in a dose-dependent manner with an IC50 value of 77.2 μM. In addition, 7-acetoxydehydroaustinol (2) and four other known meroterpenoids (5, 7, 9, and 10) weakly suppressed the overproduction of nitric oxide in lipopolysaccharide-challenged BV2 microglial cells with IC50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively.
Rational design of syn-safencin, a novel linear antimicrobial peptide derived from the circular bacteriocin safencin AS-48 J. Antibiot. (IF 2.033) Pub Date : 2018-02-20 Francisco R. Fields, Katelyn E. Carothers, Rashna D. Balsara, Victoria A. Ploplis, Francis J. Castellino, Shaun W. Lee
Bacteriocins hold unprecedented promise as a largely untapped source of antibiotic alternatives in the age of multidrug resistance. Here, we describe the first approach to systematically design variants of a novel AS-48 bacteriocin homologue, which we have termed safencin AS-48, from Bacillus safensis, to gain insights into engineering improved activity of bacteriocins. A library of synthetic peptides in which systematic amino acid substitutions to vary the periodicity and abundance of polar, acidic, aliphatic, and hydrophobic residues were generated for a total of 96 novel peptide variants of a single bacteriocin candidate. Using this method, we identified nine synthetic safencin (syn-safencin) variants with broad and potent antimicrobial activities with minimal inhibitory concentrations (MIC) as low as 250 nM against E. coli, P. aeruginosa, X. axonopodis, and S. pyogenes with minimal cytotoxicity to mammalian cells. It is anticipated that the strategies we have developed will serve as general guides for tuning the specificity of a given natural bacteriocin compound for therapeutic specificity.
Dipyrimicin A and B, microbial compounds isolated from Amycolatopsis sp. K16-0194 J. Antibiot. (IF 2.033) Pub Date : 2018-02-20 Shoko Izuta, Shohei Kosaka, Makoto Kawai, Rei Miyano, Hirotaka Matsuo, Atsuko Matsumoto, Kenichi Nonaka, Yōko Takahashi, Satoshi Ōmura, Takuji Nakashima
In a search for compounds interacting with ergosterol resin, a new compound named dipyrimicin B was isolated from a rare actinomycete strain, Amycolatopsis sp. K16-0194. In addition, another analog, dipyrimicin A, which does not interact with the resin, was also discovered. The structures of the two dipyrimicins were established by comprehensive 1D and 2D NMR and MS analyses and found to contain a unique core structure, a 2,2′-bipyridine skeleton. Dipyrimicin A showed strong antimicrobial and cytotoxic activity, whereas dipyrimicin B displayed distinctly poor antimicrobial and cytotoxic activities.
Anti-Helicobacter pylori activities of selected N-substituted cinnamamide derivatives evaluated on reference and clinical bacterial strains J. Antibiot. (IF 2.033) Pub Date : 2018-02-13 Karolina Klesiewicz, Elżbieta Karczewska, Paweł Nowak, Iwona Skiba-Kurek, Edward Sito, Katarzyna Pańczyk, Paulina Koczurkiewicz, Dorota Żelaszczyk, Elżbieta Pękala, Anna M. Waszkielewicz, Alicja Budak, Henryk Marona, Agnieszka Gunia-Krzyżak
In this study, thirty-five N-substituted derivatives of cinnamic acid amide (cinnamamide) were evaluated for anti-Helicobacter pylori activity using an agar disc-diffusion method. Qualitative screening was performed on a reference H. pylori strain (ATCC 43504), resulting in the identification of the three most active compounds, 8 (R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide, minimal inhibitory concentration, MIC = 7.5 µg/mL), 23 ((2E)-3-(4-chlorophenyl)-N-(2-hydroxycyclohexyl)prop-2-enamide, MIC = 10 µg/mL), and 28 ((2E)-3-(4-chlorophenyl)-N-(4-oxocyclohexyl)prop-2-enamide, MIC = 10 µg/mL). These compounds were further tested on twelve well-characterized clinical strains, yielding MIC values that ranged from 10 to 1000 µg/mL. Preliminary safety assessments of the compounds were made using the MTT viability test for cytotoxicity and Ames test for mutagenicity, which showed them to be generally safe, although compounds 8 and 28 showed mutagenic activity at some of the tested concentrations. The results of this study showed the anti-H. pylori potential of cinnamamide derivatives.
In vitro activity of minocycline combined with aminoglycosides against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae J. Antibiot. (IF 2.033) Pub Date : 2018-02-07 Ni Wentao, Li Guobao, Zhao Jin, Cui Junchang, Wang Rui, Gao Zhancheng, Liu Youning
This study assessed the in vitro antibacterial activity of minocycline-aminoglycoside combination against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Seventy non-duplicate clinical isolates of KPC-producing K. pneumoniae were collected from patients with bloodstream infections. The synergistic activity of minocycline-aminoglycoside combination was studied by the checkerboard method and time-kill assays in strains with different susceptibilities, and the mutant prevention concentration (MPC) and mutant selection window (MSW) of drugs alone and in combination were determined. The checkerboard method found this combination displayed synergistic and partial synergistic activity against aminoglycoside-susceptible isolates, but indifferent activity against aminoglycoside-resistant isolates. Time-kill assays further demonstrated strong synergistic and bactericidal effect of this combination existed against isolates which were susceptible to both drugs. But for resistant isolates, the time-kill assays showed no synergy. The MPCs of minocycline or aminoglycosides were 8- to 32-fold higher than the MICs, suggesting the MSWs of these drugs were quite wide. For the antibiotic combinations, the addition of 1×MIC concentration of amikacin or gentamicin could reduce the MPCs of minocycline by 4- to 16-fold. Generally, no mutants recovered in the plates containing 1×MIC concentration of minocycline and 2×MIC concentration of amikacin or gentamicin. In summary, these results suggest that minocycline-aminoglycoside combination can be an alternative for infections caused by KPC-producing K. pneumoniae because this combination displays strong synergistic and bactericidal activity in susceptible isolates, and can effectively prevent the emergence of resistant mutants. Further in vitro pharmacokinetic/pharmacodynamic studies and clinical trials should be performed to fully evaluate the efficacy of this drug combination.
New phenolic bisabolane sesquiterpenoid derivatives with cytotoxicity from Aspergillus tennesseensis J. Antibiot. (IF 2.033) Pub Date : 2018-02-07 Li Liu, Ruixing Liu, Buddha Bahadur Basnet, Li Bao, Junjie Han, Long Wang, Hongwei Liu
Three new bisabolane sesquiterpenoid esters, aspertenols A–B (1–3), and six known compounds (4–9) were isolated from the fungus Aspergillus tennesseensis. The structures of new compounds were elucidated by extensive spectroscopic analysis. The cytotoxicities of 1–9 against A549, K562, and ASPC cell lines were tested by using the CCK8 method. Compounds 1, 3, 4, 6, 7, and 9 showed inhibition on K562 cell line with IC50 values in the range from 16.6 to 72.7 μM. Compounds 1, 4, and 9 showed moderate inhibitory activity against A549 with IC50 of 43.5, 70.2, and 61.1 μM, respectively.
Rifaximin decreases virulence of Crohn’s disease-associated Escherichia coli and epithelial inflammatory responses J. Antibiot. (IF 2.033) Pub Date : 2018-02-06 Belgin Dogan, Jing Fu, Shiying Zhang, Ellen J. Scherl, Kenneth W. Simpson
Escherichia coli with an adherent and invasive pathotype (AIEC) is implicated in the pathogenesis of Crohn’s disease (CD). Rifaximin improves symptoms in mild-to-moderate CD. It is unclear if this outcome is due to its effects on bacteria or intestinal epithelial inflammatory responses. We examined the effects of rifaximin on the growth and virulence of CD-associated E. coli and intestinal epithelial inflammatory responses. Seven well-characterized CD-associated E. coli strains (six AIEC, one non-AIEC; four rifaximin-resistant, three sensitive) were evaluated. We assessed the effects of rifaximin on CD-associated E. coli growth, adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and survival in macrophages. Additionally, we determined the effects of rifaximin on intestinal epithelial inflammatory responses. In vitro rifaximin exerted a dose-dependent effect on the growth of sensitive strains but did not affect the growth of resistant strains. Rifaximin reduced adhesion, invasion, virulence gene expression and motility of CD-associated E. coli in a manner that was independent of its antimicrobial effect. Furthermore, rifaximin reduced IL-8 secretion from pregnane X receptor-expressing T84 colonic epithelial cells. The effect of rifaximin on adhesion was largely attributable to its action on bacteria, whereas decreases in invasion and cytokine secretion were due to its effect on the epithelium. In conclusion, our results show that rifaximin interferes with multiple steps implicated in host-AIEC interactions related to CD, including adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and pro-inflammatory cytokine secretion. Further study is required to determine the relationship of these effects to clinical responses in CD patients.
Kinanthraquinone, a new anthraquinone carboxamide isolated from Streptomyces reveromyceticus SN-593-44 J. Antibiot. (IF 2.033) Pub Date : 2018-02-06 Hiroshi Takagi, Toshihiko Nogawa, Yushi Futamura, Shunji Takahashi, Hiroyuki Osada
A new anthraquinone derivative, kinanthraquinone (1) was isolated from Streptomyces reveromyceticus SN-593-44. Its structure was determined by the combination of spectroscopic methods including NMR and MS. Kinanthraquinone had a characteristic carboxamide group and was a rare class of metabolite as an anthraquinone derivative isolated from microbes. It showed moderate cytotoxocity against HL-60 and srcts-NRK cell with IC50 value of 7.9 and 10 μM, respectively.
Rationale and design of an inhibitor of RecA protein as an inhibitor of Acinetobacter baumannii J. Antibiot. (IF 2.033) Pub Date : 2018-02-06 Vishvanath Tiwari, Monalisa Tiwari, Deepika Biswas
Acinetobacter baumannii is one of the ESKAPE pathogen, which causes pneumonia, urinary tract infections, and is linked to high degree of morbidity and mortality. One-way antibiotic and disinfectant resistance is acquired by the activation of RecA-mediated DNA repair (SOS-response) that maintain ROS-dependent DNA damage caused by these anti-bacterial molecules. To increase the efficacy of different anti-microbial, there is a need to design an inhibitor against RecA of A. baumannii. We have performed homology modeling to generate the structure of RecA, followed by model refinement and validation. High-throughput virtual screening of 1,80,313 primary and secondary metabolites against RecA was performed in HTVS, SP, and XP docking modes. The selected 195 compounds were further analyzed for binding free energy by molecular mechanics approach. The selected top two molecules from molecular mechanics approach were further validated by molecular dynamics simulation (MDS). In-silico high-throughput virtual screening and MDS validation identified ZINC01530654 or (+−)-2-((4-((7-Chloro-4-quinolyl)amino)pentyl)ethylamino)ethanol sulfate (or hydroxychloroquine sulfate) as a possible lead molecule binding to RecA protein. We have experimentally determined the mechanism of ZINC01530654 to RecA protein. These findings suggest a strategy to chemically inhibit the vital process controlled by RecA that could be helpful for the development of new antibacterial agents.
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