Spiciferone analogs from an endophytic fungus Phoma betae collected from desert plants in West China J. Antibiot. (IF 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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 2.237) 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.
Kanamycin and its derivative, arbekacin: significance and impact J. Antibiot. (IF 2.237) Pub Date : 2018-02-05 Kunimoto Hotta, Shinichi Kondo
On the occasion of the 60th anniversary of the discovery (1957) of kanamycin (KM), a series of research achievements on KM and its semisynthetic derivative Arbekacin (ABK) are outlined. KM was first used clinically in 1958 and was appreciated for its remarkable curing effect on various bacterial infections, especially tuberculosis. ABK is a KM derivative rationally semisynthesized to overcome KM resistance due to enzymatic phosphorylation and acetylation. Since its approval in 1990 as an anti-MRSA drug, ABK has been and still is effectively used in chemotherapy because MRSA rarely develops high ABK-resistance. Research that illuminated the unique features of ABK enabling it to resist the development of resistance by MRSA are also described.
Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria J. Antibiot. (IF 2.237) Pub Date : 2017-11-29 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
Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria, Published online: 29 November 2017; doi:10.1038/ja.2017.145 Halistanol sulfates I and J, new SIRT1–3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria
Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster J. Antibiot. (IF 2.237) Pub Date : 2017-11-29 Kirk A Reynolds, Hanna Luhavaya, Jie Li, Samira Dahesh, Victor Nizet, Kazuya Yamanaka, Bradley S Moore
Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster, Published online: 29 November 2017; doi:10.1038/ja.2017.146 Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster
Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4 J. Antibiot. (IF 2.237) Pub Date : 2017-11-15 Hideki Hashizume, Kiyoko Iijima, Kazuma Yamashita, Tomoyuki Kimura, Shun-ichi Wada, Ryuichi Sawa, Masayuki Igarashi
Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4 Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4, Published online: 15 November 2017; doi:10.1038/ja.2017.135
Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168-141F8 J. Antibiot. (IF 2.237) Pub Date : 2017-11-15 Ryuichi Sawa, Yumiko Kubota, Maya Umekita, Masaki Hatano, Chigusa Hayashi, Masayuki Igarashi
Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168-141F8 Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168-141F8, Published online: 15 November 2017; doi:10.1038/ja.2017.140
Synthesis and antibacterial activity of novel lincomycin derivatives. IV. Optimization of an N-6 substituent J. Antibiot. (IF 2.237) Pub Date : 2017-11-08 Ko Kumura, Yoshinari Wakiyama, Kazutaka Ueda, Eijiro Umemura, Yoko Hirai, Keiko Yamada, Keiichi Ajito
The design and synthesis of lincomycin derivatives modified at the C-6 and C-7 positions are described. A substituent at the C-7 position is a 5-aryl-1,3,4-thiadiazol-2-yl-thio group that generates antibacterial activities against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes carrying an erm gene. An additional modification at the C-6 position was explored in application of information regarding pirlimycin and other related compounds. These dual modifications were accomplished by using methyl α-thiolincosaminide as a starting material. As a result of these dual modifications, the antibacterial activities were improved compared with those of compounds with a single modification at the C-7 position. The antibacterial activities of selected compounds in this report against macrolide-resistant S. pneumoniae and S. pyogenes with an erm gene were superior to those of telithromycin.
Incentivising innovation in antibiotic drug discovery and development: progress, challenges and next steps J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Victoria L Simpkin, Matthew J Renwick, Ruth Kelly, Elias Mossialos
Political momentum and funding for combatting antimicrobial resistance (AMR) continues to build. Numerous major international and national initiatives aimed at financially incentivising the research and development (R&D) of antibiotics have been implemented. However, it remains unclear how to effectively strengthen the current set of incentive programmes to further accelerate antibiotic innovation. Based on a literature review and expert input, this study first identifies and assesses the major international, European Union, US and UK antibiotic R&D funding programmes. These programmes are then evaluated across market and public health criteria necessary for comprehensively improving the antibiotic market. The current set of incentive programmes are an important initial step to improving the economic feasibility of antibiotic development. However, there appears to be a lack of global coordination across all initiatives, which risks duplicating efforts, leaving funding gaps in the value chain and overlooking important AMR goals. This study finds that incentive programmes are overly committed to early-stage push funding of basic science and preclinical research, while there is limited late-stage push funding of clinical development. Moreover, there are almost no pull incentives to facilitate transition of antibiotic products from early clinical phases to commercialisation, focus developer concentration on the highest priority antibiotics and attract large pharmaceutical companies to invest in the market. Finally, it seems that antibiotic sustainability and patient access requirements are poorly integrated into the array of incentive mechanisms.
Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Yoshinari Wakiyama, Ko Kumura, Eijiro Umemura, Satomi Masaki, Kazutaka Ueda, Yasuo Sato, Yoko Hirai, Yoshio Hayashi, Keiichi Ajito
In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4′-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4′-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.
New antituberculous drugs derived from natural products: current perspectives and issues in antituberculous drug development J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Masayuki Igarashi, Yoshimasa Ishizaki, Yoshiaki Takahashi
Tuberculosis is one of the most common and challenging infectious diseases worldwide. Especially, the lack of effective chemotherapeutic drugs for tuberculosis/human immunodeficiency virus co-infection and prevalence of multidrug-resistant and extensively drug-resistant tuberculosis remain to be serious clinical problems. Development of new drugs is a potential solution to fight tuberculosis. In this decade, the development status of new antituberculous drugs has been greatly advanced by the leading role of international organizations such as the Global Alliance for Tuberculosis Drug Development, Stop Tuberculosis Partnership and Global Health Innovative Technology Fund. In this review, we introduce the development status of new drugs for tuberculosis, focusing on those derived from natural products.
Self-control of the PHO regulon: the PhoP-dependent protein PhoU controls negatively expression of genes of PHO regulon in Streptomyces coelicolor J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Seomara Martín-Martín, Antonio Rodríguez-García, Fernando Santos-Beneit, Etelvina Franco-Domínguez, Alberto Sola-Landa, Juan Francisco Martín
Phosphate control of the biosynthesis of secondary metabolites in Streptomyces is mediated by the two component system PhoR–PhoP. Linked to the phoR–phoP cluster, and expressed in the opposite orientation, is a phoU-like encoding gene with low identity to the phoU gene of Escherichia coli. Expression of this phoU-like gene is strictly dependent on PhoP activation. We have isolated a PhoU-null mutant and used transcriptomic and RNA-sequencing (RNA-seq) procedures to identify its transcription start site and regulation. RNA-seq studies identified two transcription start sites, one upstream of phoU and the second upstream of the mptA gene. Whereas transcription of PhoU is entirely dependent on PhoP, expression of the downstream mtpA gene is only partially dependent on PhoP activation. The phoU mutant grows more slowly than the parental strain, sporulates poorly and the spores lack pigmentation. Production of actinorhodin and undecylprodigiosin decreased in the phoU mutant, indicating that PhoU has a positive modulating effect on production of these antibiotics. Indeed, transcriptional studies of expression of the actII-ORF4 and redD genes indicated that the PhoU protein activates expression of these antibiotic regulators. Using the glpQ1 promoter as in vivo reporter of the activity of the PHO regulon genes, we observed that expression of glpQ1 is negatively modulated by PhoU. These results were confirmed by reverse transcription-PCR studies of three genes of the PHO regulon; that is, glpQ1, pstS and phoR. In conclusion, PhoU acts as a negative modulator of expression of the PHO regulon genes and as phoU expression is strictly dependent on PhoP activation, this mechanism appears to work as a feed-back control mechanism (self-regulation).
Selective catalytic hydrogenation of the N-acyl and uridyl double bonds in the tunicamycin family of protein N-glycosylation inhibitors J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Neil PJ Price, Michael A Jackson, Karl E Vermillion, Judith A Blackburn, Jiakun Li, Biao Yu
Tunicamycin is a Streptomyces-derived inhibitor of eukaryotic protein N-glycosylation and bacterial cell wall biosynthesis, and is a potent and general toxin by these biological mechanisms. The antibacterial activity is dependent in part upon a π-π stacking interaction between the tunicamycin uridyl group and a specific Phe residue within MraY, a tunicamycin-binding protein in bacteria. We have previously shown that reducing the tunicamycin uridyl group to 5,6-dihydrouridyl (DHU) significantly lowers its eukaryotic toxicity, potentially by disrupting the π-stacking with the active site Phe. The present report compares the catalytic hydrogenation of tunicamycin and uridine with various precious metal catalysts, and describe optimum conditions for the selective production of N-acyl reduced tunicamycin or for tunicamycins reduced in both the N-acyl and uridyl double bonds. At room temperature, Pd-based catalysts are selective for the N-acyl reduction, whereas Rh-based catalysts favor the double reduction to provide access to fully reduced tunicamycin. The reduced DHU is highly base-sensitive, leading to amide ring opening under mild alkaline conditions.
Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Hayamitsu Adachi, Koichi Nakae, Shuichi Sakamoto, Chisato Nosaka, Sonoko Atsumi, Masabumi Shibuya, Nobuaki Higashi, Motowo Nakajima, Tatsuro Irimura, Yoshio Nishimura
Microbial metabolites have attracted increasing interest as a source of therapeutics and as probes for biological mechanisms. New microbial metabolites and derivatives targeted at inflammation and bone disease therapy have been identified by focusing on prostaglandin release, osteoblast differentiation and immune cell functions. These modulators of inflammatory processes and bone disease contribute to our understanding of biological mechanisms and support identification of the therapeutic potential of drug lead candidates. The present review describes recent advances in the chemistry and analysis of inhibitors of prostaglandin release or other functional molecules of immune cells, as well as inducers of osteoblast differentiation, including biological and pharmacological activities.
Cellular uptake of modified aminoglycosides J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Kaivin Hadidi, Ezequiel Wexselblatt, Jeffrey D Esko, Yitzhak Tor
The uptake of modified amino- and guanidino-glycosides derived from kanamycin, tobramycin and neomycin in native and mutant CHO cells is examined using confocal microscopy and flow cytometry, illustrating the significance of multivalency for mammalian cell internalization of carriers that specifically interact with cell surface heparan sulfate proteoglycans.
Our microbes not only produce antibiotics, they also overproduce amino acids J. Antibiot. (IF 2.237) Pub Date : 2017-11-01 Sergio Sanchez, Romina Rodríguez-Sanoja, Allison Ramos, Arnold L Demain
Fermentative production of amino acids is an important goal of modern biotechnology. Through fermentation, micro-organisms growing on inexpensive carbon and nitrogen sources can produce a wide array of valuable products including amino acids. The amino acid market is $8 billion and mainly impacts the food, pharmaceutical and cosmetics industries. In terms of tons of amino acids produced per year by fermentation, L-glutamate is the most important amino acid produced (3.3 million), followed by L-lysine (2.2 million). The bacteria producing these amino acids are among the top fermentation organisms with respect to titers. Corynebacterium glutamicum is the best producer.
New eremophilane and dichlororesorcinol derivatives produced by endophytes isolated from Ficus ampelas J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Yoshihito Shiono, Niken Istikhari Muslihah, Takuma Suzuki, Nanang Rudianto Ariefta, Chairil Anwar, Handojo Hadi Nurjanto, Takako Aboshi, Tetsuya Murayama, Keitaro Tawaraya, Takuya Koseki, Jun Yoshida, Narandulam Usukhbayar, Shota Uesugi, Ken-ichi Kimura
The novel compound, 11-O-methylpetasitol (1), was isolated from Penicillium sp. N-175-1, and two new compounds, cosmochlorins D (5) and E (6), were isolated from Phomopsis sp. N-125. In addition, three known eremophilane sesquiterpenes, sporogen-AO1 (2), petasol (3) and 6-dehydropetasol (4), were isolated from Penicillium sp. N-175-1. The structures of 1, 5 and 6 were elucidated by a combination of extensive spectroscopic analyses, including 2D NMR, high-resolution electrospray ionization time-of-flight mass spectrometry (HRESITOFMS) and chemical reactions. Compounds 2, 3, 5 and 6 exhibited cytotoxicity to HL60 and 2 and 3 to HeLa cells. Furthermore, 2 and 3 showed robust growth-restoring activity of a Saccharomyces cerevisiae (cdc2-1 rad9Δ) mutant strain, whereas 5 and 6 exhibited minor growth-restoring activity in this strain. Thus, these compounds may inhibit the growth of HL60 and HeLa cells by blocking the cell cycle, and they may be utilized as new lead compounds that act as inhibitors of survival signal transduction pathways.
Enantiospecific total synthesis of the squalene synthase inhibitors (–)-CJ-13,982 and its enantiomer from a common intermediate J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Dayna Sturgess, Zongjia Chen, Jonathan M White, Mark A Rizzacasa
The total syntheses of both the natural and unnatural enantiomers of the alkyl citrate natural product CJ-13,982 (1) from the common d-ribose-derived acid 6 are described.
A new eremophilane sesquiterpene from the fungus Xylaria sp. V-27 and inhibition activity against degranulation in RBL-2H3 cells J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Abdou Tchoukoua, Takuma Suzuki, Nanang Rudianto Ariefta, Takuya Koseki, Yusuke Okawa, Ken-ichi Kimura, Yoshihito Shiono
A new eremophilane sesquiterpene, 13,13-dimethoxyintegric acid (1), together with known compound integric acid (2) have been isolated from a fungus, Xylaria sp. V-27, obtained from a dead branch. The structure of 1 was established by means of spectroscopic analyses. 1 and 2 promoted growth restoring activity against the mutant yeast strain (Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ)) and inhibited degranulation of rat basophilic leukemia RBL-2H3 cells stimulated by immnunoglobulin G + 2,4-dinitrophenylated-bovine serum albumin (IgE+DNP-BSA), thapsigargin and A23187.
Destination of aminoglycoside antibiotics in the ‘post-antibiotic era’ J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Yoshiaki Takahashi, Masayuki Igarashi
Aminoglycoside antibiotics (AGAs) were developed at the dawn of the antibiotics era and have significantly aided in the treatment of infectious diseases. Aminoglycosides have become one of the four major types of antibiotics in use today and, fortunately, still have an important role in the clinical treatment of severe bacterial infections. In this review, the current usage, modes of action and side effects of AGAs, along with the most common bacterial resistance mechanisms, are outlined. Finally, the recent development situation and possibility of new AGAs in the ‘post-antibiotic era’ are considered.
Phenazine carboxylic acid and its derivative induce osteoblast differentiation in preosteoblastic MC3T3-E1 cells but adipocyte differentiation in pluripotent mesenchymal C3H10T1/2 cells J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Shuichi Sakamoto, Takumi Watanabe, Yasuko Kohda, Masatomi Iijima, Ryuichi Sawa, Maiko Okada, Hayamitsu Adachi, Yoshio Nishimura, Manabu Kawada
Osteoblast and adipocyte are differentiated from mesenchymal stem cells and dysregulation of the differentiation might result in disease, such as osteoporosis and diabetes. To find small compounds that induce osteoblast differentiation, we screened an in-house natural compounds library with mouse preosteoblastic MC3T3-E1 cells using alkaline phosphatase (ALP) expression as an early osteoblast marker. We found that phenazine-1-carboxylic acid (PCA), one of the major phenazine derivatives produced by Pseudomonas, induced osteoblast differentiation in the cells at micromolar concentrations. PCA acted synergistically with an agonist of hedgehog signaling in inducing ALP activity in the cells. We also found that 2-hydroxy-PCA (2H-PCA) induced osteoblast differentiation in the cells but 2-methoxy-PCA and 1-hydroxy-phenazine did not. Unexpectedly, treatment of mouse pluripotent mesenchymal C3H10T1/2 cells with PCA or 2H-PCA induced an obvious morphological change. Oil Red O staining and real-time reverse-transcription PCR analysis revealed that PCA induced not osteoblast differentiation but adipocyte differentiation in C3H10T1/2 cells. These compounds could allow us to investigate the mechanism of osteoblast and adipocyte differentiation in the two model cell systems through a chemical biology approach.
Challenges and discoveries in the total synthesis of complex polyketide natural products J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Ian Paterson, Nelson Yuen Sum Lam
Structurally complex polyketide natural products, isolated from a variety of marine and terrestrial sources, continue to provide a valuable source of rewarding targets for the synthetic chemist to tackle. In this account, we provide an overview of the total synthesis of several structurally fascinating polyketides with promising anticancer activity completed in our group based on our versatile asymmetric aldol methodology—spirastrellolide A methyl ester, leiodermatolide, rhizopodin and chivosazole F—and highlight the unanticipated challenges and discoveries encountered.
Lanostane triterpenoids from fruiting bodies of basidiomycete Stereum sp., structures and biological activities J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Jian-Neng Yao, Lin Chen, Yang Tang, He-Ping Chen, Zhen-Zhu Zhao, Zheng-Hui Li, Tao Feng, Ji-Kai Liu
Twelve new lanostane triterpenoids, sterenoids A–L (1–12) have been isolated from fruiting bodies of the basidiomycete Stereum sp. Compounds 1–12 are rare 14(13→12)abeo-lanostane triterpenoids featuring remarkable 13R configurations that discriminate from the previously covered counterparts. Their structures and absolute configurations are assigned on the basis of in-depth one- and two-dimensional NMR spectroscopic analysis, as well as unbiased quantum chemical NMR and electronic CD calculations. All isolates are evaluated for their in vitro cytotoxicity against five human tumor cell lines. Compound 5 exhibits potent cytotoxic activities against tumor cell lines HL-60 and SMMC-7721 with IC50 values of 4.7 and 7.6 μM, respectively.
Amycolatopsins A–C: antimycobacterial glycosylated polyketide macrolides from the Australian soil Amycolatopsis sp. MST-108494 J. Antibiot. (IF 2.237) Pub Date : 2017-10-25 Zeinab G Khalil, Angela A Salim, Daniel Vuong, Andrew Crombie, Ernest Lacey, Antje Blumenthal, Robert J Capon
A southern Australian soil isolate, Amycolatopsis sp. MST-108494, was subjected to a panel of fermentation and media optimization trials, supported by analytical chemical profiling, to detect and enhance production of a rare class of secondary metabolites. Chemical fractionation of two complementary fermentations yielded three new polyketides, identified by detailed spectroscopic analysis as the glycosylated macrolactones, amycolatopsins A (1), B (2) and C (3), closely related to the ammocidins and apoptolidins. Amycolatopsins 1 and 3 selectively inhibited growth of Mycobacterium bovis (BCG) and Mycobacterium tuberculosis (H37Rv) when compared with other Gram-positive or Gram-negative bacteria, with 3 exhibiting low levels of cytotoxicity toward mammalian cells. Thus, our data reveal promising structure activity relationship correlations where the antimycobacterial properties of amycolatopsins are enhanced by hydroxylation of the 6-Me (that is, 1 and 3), whereas mammalian cytotoxicity is decreased by hydrolysis of the disaccharide moiety (that is, 3).
Current landscape and future prospects of antiviral drugs derived from microbial products J. Antibiot. (IF 2.237) Pub Date : 2017-10-11 Naoki Takizawa, Manabu Yamasaki
Viral infections are a major global health threat. Over the last 50 years, significant efforts have been devoted to the development of antiviral drugs and great success has been achieved for some viruses. However, other virus infections, such as epidemic influenza, still spread globally and new threats continue to arise from emerging and re-emerging viruses and drug-resistant viruses. In this review, the contributions of microbial products isolated in Institute of Microbial Chemistry for antiviral research are summarized. In addition, the current state of development of antiviral drugs that target influenza virus and hepatitis B virus, and the future prospects for antivirals from natural products are described and discussed.
Large-scale preparation of key building blocks for the manufacture of fully synthetic macrolide antibiotics J. Antibiot. (IF 2.237) Pub Date : 2017-10-11 Philip C Hogan, Chi-Li Chen, Kristen M Mulvihill, Jonathan F Lawrence, Eric Moorhead, Jens Rickmeier, Andrew G Myers
Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.
Anthraquinones from the saline-alkali plant endophytic fungus Eurotium rubrum J. Antibiot. (IF 2.237) Pub Date : 2017-10-11 Yonggang Zhang, Airong Jia, Huabin Chen, Menghua Wang, Gang Ding, Liyan Sun, Li Li, Meixue Dai
Saline-alkali plant endophytes similar as marine mangrove plant-derived ones are a big member of microbes inhabiting in tissues of plants without causing obvious disease to their hosts, and they must adapt to the extreme environment of high osmolarity and nutrient deprivation in plant, which are different from terrestrial plant endophytes. Owing to the unique bio-environments, endophytes originated from mangrove plants are being considered as a new resource of natural product research and diverse secondary metabolites with a wide range of bioactivities have been isolated. Compared with those of marine mangrove plant-derived endophytes, chemical investigation of saline-alkali plant-derived endophytic fungi have just begun, and only several natural products were isolated from these unique environmental fungi.Suaeda salsa L.
Ascosteroside D, a new mitochondrial respiration inhibitor discovered by pesticidal screening using insect ADP/ATP carrier protein-expressing Saccharomyces cerevisiae J. Antibiot. (IF 2.237) Pub Date : 2017-10-11 Yoshihiro Watanabe, Yukihiro Asami, Satomi Narusawa, Shohei Hashimoto, Masato Iwatsuki, Kenichi Nonaka, Yasuo Shinohara, Takahiro Shiotsuki, Naoya Ichimaru, Hideto Miyoshi, Satoshi Ōmura, Kazuro Shiomi
A new lanostane-type triterpenoid, ascosteroside D, was isolated from a fungus, Aspergillus sp. FKI-6682. It inhibited insect ADP/ATP carrier protein (AAC)-expressing Saccharomyces cerevisiae in glycerol-containing medium, but did not inhibit Δaac S. cerevisiae in glucose-containing medium. It is hypothesized that ascosteroside D inhibits ATP production in mitochondria.
Biological activity of intervenolin analogs with a phenyl substituent J. Antibiot. (IF 2.237) Pub Date : 2017-10-11 Hikaru Abe, Manabu Kawada, Masayuki Igarashi, Shun-ichi Ohba, Chigusa Hayashi, Chiharu Sakashita, Takumi Watanabe, Masakatsu Shibasaki
Intervenolin analogs with a phenyl substituent at the 2- or 3-position were synthesized. The compounds (3–11) showed weak or no inhibitory activity toward the growth of MKN-74 gastric adenocarcinoma cells, even in the presence or absence of the corresponding Hs738 stromal cells, whereas 2-substituted analogs exhibited selective anti-Helicobacter pylori activity. Introduction of a pendant side chain on the nitrogen alleviated their acute toxicity in mice. The 2-phenyl-substituted analogs are reasonable structural templates for structure–activity relationship studies toward the development of anti-H. pylori agents that do not affect human cells.
Bisoxazolomycin A: a new natural product from ‘Streptomyces subflavus subsp. irumaensis’ AM-3603 J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Wilaiwan Koomsiri, Yuki Inahashi, Tōru Kimura, Kazuro Shiomi, Yōko Takahashi, Satoshi Ōmura, Arinthip Thamchaipenet, Takuji Nakashima
Bisoxazolomycin (1), oxazolomycin A2 (2) and oxazolomycin A (3) were identified by physicochemical screening approach from a culture broth of ‘Streptomyces subflavus subsp. irumaensis’ AM-3603. Compound 2 is a hydrolyzed analog of 3 at the β-lactone ring, and 1 is a new dimeric analog of 2. Compounds 1 and 2 exhibited less potent antibacterial activity and cytotoxicity than 3, which might be due to lack of the β-lactone ring.
Pteridic acids C–G spirocyclic polyketides from the marine-derived Streptomyces sp. SCSGAA 0027 J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Xu-Hua Nong, Xiao-Yi Wei, Shu-Hua Qi
Five new pteridic acids C–G (1–5) were isolated from a culture broth of the marine-derived actinomycete Streptomyces sp. SCSGAA 0027. Their complete structures were elucidated on the basis of NMR data, modified Mosher’s method and quantum chemical calculations. Furthermore, their cytotoxicity, antiviral and antimicrobial activities were also evaluated.
Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Junichi Taira, Koji Morita, Shotaro Kawashima, Tomohiro Umei, Hiroki Baba, Taira Maruoka, Hideyuki Komatsu, Hiroshi Sakamoto, James C Sacchettini, Shunsuke Aoki
The enzymes responsible for biotin biosynthesis in mycobacteria have been considered as potential drug targets owing to the important role in infection and cell survival that the biotin synthetic pathway plays in Mycobacterium tuberculosis. Among the enzymes that comprise mycobacterium biotin biosynthesis systems, 7,8-diaminopelargonic acid synthase (DAPAS) plays an essential role during the stationary phase in bacterial growth. In this study, compounds that inhibit mycobacterial DAPAS were screened in the virtual chemical library using an in silico structure-based drug screening (SBDS) technique, and the antimycobacterial activity of the selected compounds was validated experimentally. The DOCK–GOLD programs utilized by in silico SBDS facilitated the identification of a compound, referred to as KMD6, with potent inhibitory effects on the growth of model mycobacteria (M. smegmatis). The subsequent compound search, which was based on the structural features of KMD6, resulted in identification of three additional active compounds, designated as KMDs3, KMDs9 and KMDs10. The inhibitory effect of these compounds was comparable to that of isoniazid, which is a first-line antituberculosis drug. The high antimycobacterial activity of KMD6, KMDs9 and KMDs10 was maintained on the experiment with M. tuberculosis. Of the active compounds identified, KMDs9 would be a promising pharmacophore, owing to its long-term antimycobacterial effect and lack of cytotoxicity.
Synthetic studies of viridiofungins, broad-spectrum antifungal agents and serine palmitoyl transferase inhibitors J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Naoya Kumagai, Masakatsu Shibasaki
Viridiofungins are alkyl citrate natural products characterized by their inhibitory effects on squalene synthase and serine palmitoyl transferase. Their activities as broad-spectrum antifungal agents as well as blocking agents for the biosynthesis of sphingolipids have inspired the development of several approaches toward their stereoselective total synthesis. Structurally, these natural products are a family of hybrid molecules comprising a longer alkyl chain and a citric acid unit, rendering an asymmetric structure that is difficult to access. Herein, we summarize the synthetic approaches to this attractive class of natural products, including proficient synthetic strategies for constructing the densely and chirally functionalized citric acid unit with high polarity. Particular emphasis is placed on methods for furnishing stereogenic centers in the highly constrained carbon framework.
Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of β-lactams J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Neil PJ Price, Trina M Hartman, Jiakun Li, Kiran K Velpula, Todd A Naumann, Maheedhara R Guda, Biao Yu, Kenneth M Bischoff
Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of β-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the β-lactams.
Chemotherapeutics overcoming nonsense mutation-associated genetic diseases: medicinal chemistry of negamycin J. Antibiot. (IF 2.237) Pub Date : 2017-09-27 Akihiro Taguchi, Keisuke Hamada, Yoshio Hayashi
Nonsense mutations caused by the presence of an in-frame premature termination codon (PTC) account for ~10% of gene lesions that together cause over 1800 inherited human diseases. One approach to treating genetic diseases that stem from PTCs is selective promotion of translational readthrough in a PTC using ‘readthrough compounds’ that can lead to partial restoration of full-length functional protein expression. (+)-Negamycin, a natural dipeptide-like antibiotic, may restore some dystrophin expression in the skeletal muscles of mice with Duchenne muscular dystrophy, and this compound has been recognized as a potential therapeutic agent for diseases caused by nonsense mutations. In an effort to develop new candidate molecules with improved activities, we established the efficient total synthesis in eight steps of (+)-negamycin using both achiral and chiral starting material. These routes provided a deamino derivative with in vivo readthrough activity with potential for long-term treatment. In a separate approach, we discovered two natural negamycin analogs, 3-epi-deoxynegamycin and its leucine derivative, which are potent readthrough compounds effective against nonsense mutations of eukaryotes but not prokaryotes. These compounds fail to display antimicrobial activity. More potent derivatives, whose structure is derived from 3-epi-deoxynegamycin, were identified and their chemistry is discussed in this review.
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.
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.
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.
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.
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.
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.
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.
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