Synthesis and Antimicrobial Activity of 4-Chloro-3-Nitrophenylthiourea Derivatives Targeting Bacterial Type II Topoisomerases

2016 ◽  
Vol 87 (6) ◽  
pp. 905-917 ◽  
Author(s):  
Anna Bielenica ◽  
Karolina Stępień ◽  
Agnieszka Napiórkowska ◽  
Ewa Augustynowicz-Kopeć ◽  
Sylwester Krukowski ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Type Ii ◽  
Bacterial Type

scholarly journals Engineered Biosynthesis of a Novel Amidated Polyketide, Using the Malonamyl-Specific Initiation Module from the Oxytetracycline Polyketide Synthase

2006 ◽  
Vol 72 (4) ◽  
pp. 2573-2580 ◽  
Author(s):  
Wenjun Zhang ◽  
Brian D. Ames ◽  
Shiou-Chuan Tsai ◽  
Yi Tang
Keyword(s):  
Polyketide Synthase ◽  
Major Product ◽  
Polyketide Synthases ◽  
Type Ii ◽  
Streptomyces Rimosus ◽  
Aromatic Polyketides ◽  
Starter Unit ◽  
Necessary And Sufficient ◽  
Bacterial Type

ABSTRACT Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases (PKSs). Understanding the biochemistry of tetracycline PKSs is an important step toward the rational and combinatorial manipulation of tetracycline biosynthesis. To this end, we have sequenced the gene cluster of oxytetracycline (oxy and otc genes) PKS genes from Streptomyces rimosus. Sequence analysis revealed a total of 21 genes between the otrA and otrB resistance genes. We hypothesized that an amidotransferase, OxyD, synthesizes the malonamate starter unit that is a universal building block for tetracycline compounds. In vivo reconstitution using strain CH999 revealed that the minimal PKS and OxyD are necessary and sufficient for the biosynthesis of amidated polyketides. A novel alkaloid (WJ35, or compound 2) was synthesized as the major product when the oxy-encoded minimal PKS, the C-9 ketoreductase (OxyJ), and OxyD were coexpressed in CH999. WJ35 is an isoquinolone compound derived from an amidated decaketide backbone and cyclized with novel regioselectivity. The expression of OxyD with a heterologous minimal PKS did not afford similarly amidated polyketides, suggesting that the oxy-encoded minimal PKS possesses novel starter unit specificity.

scholarly journals Inhibitory Activities of Gatifloxacin (AM-1155), a Newly Developed Fluoroquinolone, against Bacterial and Mammalian Type II Topoisomerases

1998 ◽  
Vol 42 (10) ◽  
pp. 2678-2681 ◽  
Author(s):  
Masaya Takei ◽  
Hideyuki Fukuda ◽  
Tokutaro Yasue ◽  
Masaki Hosaka ◽  
Yasuo Oomori
Keyword(s):  
Hela Cell ◽  
Topoisomerase Ii ◽  
Dna Gyrase ◽  
Antibacterial Activities ◽  
Type Ii ◽  
Topoisomerase Iv ◽  
E Coli ◽  
Bacterial Enzyme ◽  
Inhibitory Activities ◽  
Bacterial Type

ABSTRACT We determined the inhibitory activities of gatifloxacin againstStaphylococcus aureus topoisomerase IV,Escherichia coli DNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 forS. aureus, r = 0.972 for E. coli, and r = 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 μg/ml for S. aureustopoisomerase IV; IC50 = 0.109 μg/ml for E. coli DNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50 = 265 μg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones against S. aureustopoisomerase IV and those against E. coli DNA gyrase (r = 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50 of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that for S. aureus topoisomerase IV and that for E. coli DNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.

scholarly journals Erratum: Corrigendum: Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Gregory S. Basarab ◽  
Gunther H. Kern ◽  
John McNulty ◽  
John P. Mueller ◽  
Kenneth Lawrence ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Type Ii ◽  
Distinct Mechanism ◽  
Bacterial Type

scholarly journals Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases

2015 ◽  
Vol 112 (50) ◽  
pp. E6844-E6851 ◽  
Author(s):  
Grace Caldara-Festin ◽  
David R. Jackson ◽  
Jesus F. Barajas ◽  
Timothy R. Valentic ◽  
Avinash B. Patel ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Functional Role ◽  
Functional Characterization ◽  
Polyketide Synthases ◽  
Type Ii ◽  
Aromatic Polyketides ◽  
Linear Poly ◽  
Bacterial Type

Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7–C12 and C9–C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7–C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: “nonreducing” ARO/CYCs, which act on nonreduced poly-β-ketones, and “reducing” ARO/CYCs, which act on cyclized C9 reduced poly-β-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

scholarly journals Identification of the Calmodulin-dependent NAD+ kinase sustaining the elicitor-induced oxidative burst in plants

2019 ◽  
Author(s):  
Elisa Dell’ Aglio ◽  
Cécile Giustini ◽  
Alexandra Kraut ◽  
Yohann Couté ◽  
Christian Mazars ◽  
...  
Keyword(s):  
Plant Physiology ◽  
Oxidative Burst ◽  
Kinase Activity ◽  
Calcium Signalling ◽  
Type Ii ◽  
Nad Kinase ◽  
Metabolic Processes ◽  
Living Organisms ◽  
Related Proteins ◽  
Bacterial Type

AbstractNADP(H) is an essential cofactor ofmultiple metabolic processes in all living organisms. While NADP+ production in plants has long been known to involve a Calmodulin (CaM)/Ca2+-dependent NAD+ kinase, the nature of the enzyme catalyzing this activity has remained enigmatic, as well as its role in plant physiology. Here, we identify an Arabidopsis P-loop ATPase (Atlg04280) with a bacterial type II zeta toxin domain, that catalyzes NADP+ production upon binding of CaM/Ca2+ to a domain located in its N-terminal region. The encoded protein (NADKc-1) is associated with the mitochondria and amplifies the elicitor-induced oxidative burst in Arabidopsis leaves representing the missing link between calcium signalling and metabolism in the response to pathogen elicitor. By analysis of various plants and algae, we show that NADKc is well conserved in the plant lineage and present in basal plants. Our data allows proposing that the CaM-dependent NAD kinase activity is only found in photosynthetic species carrying NADKc-1 related proteins, which would represent the only proteins harboring CaM-dependent NAD kinase activity in plants and algae.

scholarly journals Core architecture of a bacterial type II secretion system

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anastasia A. Chernyatina ◽  
Harry H. Low
Keyword(s):  
Outer Membrane ◽  
Cell Envelope ◽  
Type Ii Secretion ◽  
Stoichiometric Ratio ◽  
Type Ii ◽  
Secretion Systems ◽  
Modular Architecture ◽  
Membrane Complex ◽  
Negative Stain ◽  
Bacterial Type

AbstractBacterial type II secretion systems (T2SSs) translocate virulence factors, toxins and enzymes across the cell outer membrane. Here we use negative stain and cryo-electron microscopy to reveal the core architecture of an assembled T2SS from the pathogen Klebsiella pneumoniae. We show that 7 proteins form a ~2.4 MDa complex that spans the cell envelope. The outer membrane complex includes the secretin PulD, with all domains modelled, and the pilotin PulS. The inner membrane assembly platform components PulC, PulE, PulL, PulM and PulN have a relative stoichiometric ratio of 2:1:1:1:1. The PulE ATPase, PulL and PulM combine to form a flexible hexameric hub. Symmetry mismatch between the outer membrane complex and assembly platform is overcome by PulC linkers spanning the periplasm, with PulC HR domains binding independently at the secretin base. Our results show that the T2SS has a highly dynamic modular architecture, with implication for pseudo-pilus assembly and substrate loading.

scholarly journals Ungeremine effectively targets mammalian as well as bacterial type I and type II topoisomerases

2011 ◽  
Vol 21 (23) ◽  
pp. 7041-7044 ◽  
Author(s):  
Laura Casu ◽  
Filippo Cottiglia ◽  
Marco Leonti ◽  
Alessandro De Logu ◽  
Emanuela Agus ◽  
...  
Keyword(s):  
Type I ◽  
Type Ii ◽  
Bacterial Type
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