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Thiostrepton

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https://www.readbyqxmd.com/read/28930155/identification-of-agents-active-against-methicillin-resistant-staphylococcus-aureus-usa300-from-a-clinical-compound-library
#1
Hongxia Niu, Rebecca Yee, Peng Cui, Lili Tian, Shuo Zhang, Wanliang Shi, David Sullivan, Bingdong Zhu, Wenhong Zhang, Ying Zhang
Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat for effective treatment of several difficult-to-treat infections in humans. To identify potential new treatment options for MRSA infections, we screened a clinical compound library consisting of 1524 compounds using a growth inhibition assay in 96-well plates. We identified 34 agents which are either bacteriostatic or bactericidal against log-phase clinical MRSA strain USA300. Among them, 9 candidates (thonzonium, cetylpyridinium, trilocarban, benzododecinium, bithionol, brilliant green, chlorquinaldol, methylbenzethonium and green violet) are known antiseptics, 11 candidates are known antibiotics currently recommended for the treatment of MRSA...
September 20, 2017: Pathogens
https://www.readbyqxmd.com/read/28894754/natural-modulators-of-endosomal-toll-like-receptor-mediated-psoriatic-skin-inflammation
#2
REVIEW
Chao-Yang Lai, Yu-Wen Su, Kuo-I Lin, Li-Chung Hsu, Tsung-Hsien Chuang
Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28820583/processing-2-methyl-l-tryptophan-through-tandem-transamination-and-selective-oxygenation-initiates-indole-ring-expansion-in-the-biosynthesis-of-thiostrepton
#3
Zhi Lin, Jia Ji, Shuaixiang Zhou, Fang Zhang, Jiequn Wu, Yinlong Guo, Wen Liu
Thiostrepton (TSR), an archetypal member of the family of ribosomally synthesized and post-translationally modified thiopeptide antibiotics, possesses a biologically important quinaldic acid (QA) moiety within the side-ring system of its characteristic thiopeptide framework. QA is derived from an independent l-Trp residue; however, its associated transformation process remains poorly understood. We here report that during the formation of QA, the key expansion of an indole to a quinoline relies on the activities of the pyridoxal-5'-phosphate-dependent protein TsrA and the flavoprotein TsrE...
August 23, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28747433/efficient-methylation-of-c2-in-l-tryptophan-by-the-cobalamin-dependent-radical-s-adenosylmethionine-methylase-tsrm-requires-an-unmodified-n1-amine
#4
Anthony J Blaszczyk, Bo Wang, Alexey Silakov, Jackson V Ho, Squire J Booker
TsrM catalyzes the methylation of C2 in l-tryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes, but it does not catalyze the formation of 5'-deoxyadenosin-5'-yl or any other SAM-derived radical. In addition to a [4Fe-4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28692634/targeting-foxm1-improves-cytotoxicity-of-paclitaxel-and-cisplatinum-in-platinum-resistant-ovarian-cancer
#5
Gina L Westhoff, Yi Chen, Nelson N H Teng
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed...
July 7, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28588757/identification-of-neuron-selective-androgen-receptor-inhibitors
#6
Maya Otto-Duessel, Ben Yi Tew, Steven Vonderfecht, Roger Moore, Jeremy O Jones
AIM: To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS: Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors...
May 26, 2017: World Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28498253/targeting-foxm1-improves-cytotoxicity-of-paclitaxel-and-cisplatinum-in-platinum-resistant-ovarian-cancer
#7
Gina L Westhoff, Yi Chen, Nelson N H Teng
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed...
June 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28392781/a-cassette-containing-thiostrepton-gentamicin-resistance-genes-and-dif-sequences-is-effective-in-construction-of-recombinant-mycobacteria
#8
Julius Mugweru, Gaelle Makafe, Yuanyuan Cao, Yang Zhang, Bangxing Wang, Shaobo Huang, Moses Njire, Chiranjibi Chhotaray, Yaoju Tan, Xinjie Li, Jianxiong Liu, Shouyong Tan, Jiaoyu Deng, Tianyu Zhang
The genetic manipulation of Mycobacterium tuberculosis genome is limited by the availability of selection markers. Spontaneous resistance mutation rate of M. tuberculosis to the widely used kanamycin is relatively high which often leads to some false positive transformants. Due to the few available markers, we have created a cassette containing thiostrepton resistance gene (tsr) for selection in M. tuberculosis and M. bovis BCG, and gentamicin resistance gene (aacC1) for Escherichia coli and M. smegmatis mc(2)155, flanked with dif sequences recognized by the Xer system of mycobacteria...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28348156/bioluminescence-method-for-in-vitro-screening-of-plasmodium-transmission-blocking-compounds
#9
Raquel Azevedo, Marija Markovic, Marta Machado, Blandine Franke-Fayard, António M Mendes, Miguel Prudêncio
The sporogonic stage of the life cycle of Plasmodium spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis, and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. Efforts to cultivate Plasmodium mosquito stages in vitro have proved challenging and yielded only moderate success. Here, we describe a methodology that simplifies the in vitro screening of much-needed transmission-blocking (TB) compounds employing a bioluminescence-based method to monitor the in vitro development of sporogonic stages of the rodent malaria parasite Plasmodium berghei Our proof-of-principle assessment of the in vitro TB activity of several commonly used antimalarial compounds identified cycloheximide, thiostrepton, and atovaquone as the most active compounds against the parasite's sporogonic stages...
June 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28249813/induction-of-chromosome-instability-by-activation-of-yes-associated-protein-and-forkhead-box-m1-in-liver-cancer
#10
Sofia M E Weiler, Federico Pinna, Thomas Wolf, Teresa Lutz, Aman Geldiyev, Carsten Sticht, Maria Knaub, Stefan Thomann, Michaela Bissinger, Shan Wan, Stephanie Rössler, Diana Becker, Norbert Gretz, Hauke Lang, Frank Bergmann, Vladimir Ustiyan, Tatiana V Kalin, Stephan Singer, Ju-Seog Lee, Jens U Marquardt, Peter Schirmacher, Vladimir V Kalinichenko, Kai Breuhahn
BACKGROUND & AIMS: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. METHODS: We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves...
June 2017: Gastroenterology
https://www.readbyqxmd.com/read/28185110/foxm1-mediated-rfc5-expression-promotes-temozolomide-resistance
#11
Wan-Xin Peng, Xiu Han, Chun-Li Zhang, Lu Ge, Feng-Yi Du, Jie Jin, Ai-Hua Gong
Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter...
February 9, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/28115345/subinhibitory-concentrations-of-bacteriostatic-antibiotics-induce-rela-dependent-and-rela-independent-tolerance-to-%C3%AE-lactams
#12
Pavel Kudrin, Vallo Varik, Sofia Raquel Alves Oliveira, Jelena Beljantseva, Teresa Del Peso Santos, Ievgen Dzhygyr, Dominik Rejman, Felipe Cava, Tanel Tenson, Vasili Hauryliuk
The nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance, and virulence. During amino acid starvation, the Escherichia coli (p)ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p)ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p)ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA...
April 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28114286/foxm1-recruits-nuclear-aurora-kinase-a-to-participate-in-a-positive-feedback-loop-essential-for-the-self-renewal-of-breast-cancer-stem-cells
#13
N Yang, C Wang, Z Wang, S Zona, S-X Lin, X Wang, M Yan, F-M Zheng, S-S Li, B Xu, L Bella, J-S Yong, E W-F Lam, Q Liu
Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by Forkhead box subclass M1 (FOXM1) as a co-factor to transactivate FOXM1 target genes in a kinase-independent manner...
June 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28025393/peroxiredoxins-prevent-oxidative-stress-during-human-sperm-capacitation
#14
Donghyun Lee, Adel R Moawad, Tania Morielli, Maria C Fernandez, Cristian O'Flaherty
STUDY QUESTION: Do peroxiredoxins (PRDXs) control reactive oxygen species (ROS) levels during human sperm capacitation? SUMMARY ANSWER: PRDXs are necessary to control the levels of ROS generated during capacitation allowing spermatozoa to achieve fertilizing ability. WHAT IS KNOWN ALREADY: Sperm capacitation is an oxidative event that requires low and controlled amounts of ROS to trigger phosphorylation events. PRDXs are antioxidant enzymes that not only act as scavengers but also control ROS action in somatic cells...
February 10, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/27911800/an-%C3%AE-%C3%AE-hydrolase-fold-protein-in-the-biosynthesis-of-thiostrepton-exhibits-a-dual-activity-for-endopeptidyl-hydrolysis-and-epoxide-ring-opening-macrocyclization
#15
Qingfei Zheng, Shoufeng Wang, Panpan Duan, Rijing Liao, Dandan Chen, Wen Liu
Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27560135/precursor-directed-mutational-biosynthesis-facilitates-the-functional-assignment-of-two-cytochromes-p450-in-thiostrepton-biosynthesis
#16
Qingfei Zheng, Shoufeng Wang, Rijing Liao, Wen Liu
Side-ring-modified thiostrepton (TSR) derivatives that vary in their quinaldic acid (QA) substitution possess more potent biological activities and better pharmaceutical properties than the parent compound. In this work, we sought to introduce fluorine onto C-7' or C-8' of the TSR QA moiety via precursor-directed mutational biosynthesis to obtain new TSR variants. Unexpectedly, instead of the target product, the exogenous chemical feeding of 7-F-QA into the ΔtsrT mutant strain resulted in a unique TSR analog with an incomplete side-ring structure and an unoxidized QA moiety (1)...
October 21, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27448565/a-novel-validated-assay-to-support-the-discovery-of-new-anti-malarial-gametocytocidal-agents
#17
Noemí Bahamontes-Rosa, María G Gomez-Lorenzo, Joël Lelièvre, Ane Rodriguez Alejandre, María Jesus Almela, Sonia Lozano, Esperanza Herreros, Francisco-Javier Gamo
BACKGROUND: Drugs that kill or inhibit Plasmodium gametocytes in the human host could potentially synergize the impact of other chemotherapeutic interventions by blocking transmission. To develop such agents, reliable methods are needed to study the in vitro activity of compounds against gametocytes. This study describes a novel assay for characterizing the activity of anti-malarial drugs against the later stages of Plasmodium falciparum gametocyte development using real-time PCR (qPCR)...
July 22, 2016: Malaria Journal
https://www.readbyqxmd.com/read/27439614/prognostic-significance-of-foxm1-expression-and-antitumor-effect-of-foxm1-inhibition-in-synovial-sarcomas
#18
Akira Maekawa, Kenichi Kohashi, Masaaki Kuda, Kunio Iura, Takeaki Ishii, Makoto Endo, Tetsuya Nakatsura, Yukihide Iwamoto, Yoshinao Oda
BACKGROUND: Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis. Most metastatic or unresectable cases are incurable. Novel antitumor agents and precise prognostication are needed for SS patients. The protein forkhead box M1 (FOXM1), which belongs to the FOX family of transcription factors, is considered to be an independent predictor of poor survival in many cancers and sarcomas, but the prognostic implications and oncogenic roles of FOXM1 in SS are poorly understood...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27257211/complete-genome-sequence-of-thiostrepton-producing-streptomyces-laurentii-atcc-31255
#19
Katsumi Doi, Yasuhiro Fujino, Yuko Nagayoshi, Toshihisa Ohshima, Seiya Ogata
Streptomyces laurentii ATCC 31255 produces thiostrepton, a thiopeptide class antibiotic. Here, we report the complete genome sequence for this strain, which contains a total of 8,032,664 bp, 7,452 predicted coding sequences, and a G+C content of 72.3%.
2016: Genome Announcements
https://www.readbyqxmd.com/read/27162541/prognostic-significance-of-forkhead-box-m1-foxm1-expression-and-antitumor-effect-of-foxm1-inhibition-in-angiosarcoma
#20
Takamichi Ito, Kenichi Kohashi, Yuichi Yamada, Takeshi Iwasaki, Akira Maekawa, Masaaki Kuda, Daichi Hoshina, Riichiro Abe, Masutaka Furue, Yoshinao Oda
BACKGROUND: The prognosis of angiosarcoma is poor and a novel treatment option for the disease is desired. The aim of this study was to investigate the prognostic significance of Forkhead box M1 (FOXM1), a transcription factor that regulates cell-cycle progression and various crucial processes in tumor progression, and its potential as a new therapeutic target. METHODS: We investigated 125 angiosarcoma clinical samples (94 primary lesions and 31 metastatic lesions in 94 patients) and a human angiosarcoma cell line (HAMON) using immunohistochemical staining and molecular biological approaches...
2016: Journal of Cancer
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