Inhibition of Human Topoisomerases I and II by Simocyclinone D8

2012 ◽  
Vol 75 (8) ◽  
pp. 1485-1489 ◽  
Author(s):  
Lisa M. Oppegard ◽  
Thuy Nguyen ◽  
Keith C. Ellis ◽  
Hiroshi Hiasa
Keyword(s):  
Simocyclinone D8

Defining a minimum pharmacophore for simocyclinone D8 disruption of DNA gyrase binding to DNA

2014 ◽  
Vol 23 (8) ◽  
pp. 3632-3643 ◽  
Author(s):  
Lauren M. Gaskell ◽  
Thuy Nguyen ◽  
Keith C. Ellis
Keyword(s):  
Dna Gyrase ◽  
Simocyclinone D8

scholarly journals Biosynthesis of Simocyclinone D8 in an 18O2-rich Atmosphere.

2002 ◽  
Vol 55 (3) ◽  
pp. 341-342 ◽  
Author(s):  
MEIKE HOLZENKÄMPFER ◽  
AXEL ZEECK
Keyword(s):  
Simocyclinone D8

Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors

2013 ◽  
Vol 23 (21) ◽  
pp. 5874-5877 ◽  
Author(s):  
Jenson Verghese ◽  
Thuy Nguyen ◽  
Lisa M. Oppegard ◽  
Lauren M. Seivert ◽  
Hiroshi Hiasa ◽  
...  
Keyword(s):  
Natural Product ◽  
Dna Gyrase ◽  
Simocyclinone D8 ◽  
Gyrase Inhibitors

scholarly journals Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

2015 ◽  
Vol 59 (11) ◽  
pp. 6689-6695 ◽  
Author(s):  
George A. Jacoby ◽  
Marian A. Corcoran ◽  
David C. Hooper
Keyword(s):  
Protective Effect ◽  
Dna Gyrase ◽  
Molecular Probes ◽  
Protective Activity ◽  
Topoisomerase Iv ◽  
Synthetic Compounds ◽  
Target Dna ◽  
Simocyclinone D8 ◽  
Microcin B17 ◽  
Insight Into

ABSTRACTQnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes.

scholarly journals Mapping Simocyclinone D8 Interaction with DNA Gyrase: Evidence for a New Binding Site on GyrB

2009 ◽  
Vol 54 (1) ◽  
pp. 213-220 ◽  
Author(s):  
C. Sissi ◽  
E. Vazquez ◽  
A. Chemello ◽  
L. A. Mitchenall ◽  
A. Maxwell ◽  
...  
Keyword(s):  
Dna Gyrase ◽  
Coumarin Derivative ◽  
Streptomyces Antibioticus ◽  
B Subunit ◽  
Terminal Domain ◽  
Antiproliferative Agent ◽  
Gyrase A ◽  
A Subunit ◽  
The Individual ◽  
Simocyclinone D8

ABSTRACT Simocyclinone D8, a coumarin derivative isolated from Streptomyces antibioticus Tü 6040, represents an interesting new antiproliferative agent. It was originally suggested that this drug recognizes the GyrA subunit and interferes with the gyrase catalytic cycle by preventing its binding to DNA. To further characterize the mode of action of this antibiotic, we investigated its binding to the reconstituted DNA gyrase (A2B2) as well as to its GyrA and GyrB subunits and the individual domains of these proteins, by performing protein melting and proteolytic digestion studies as well as inhibition assays. Two binding sites were identified, one (anticipated) in the N-terminal domain of GyrA (GyrA59) and the other (unexpected) at the C-terminal domain of GyrB (GyrB47). Stabilization of the A subunit appears to be considerably more effective than stabilization of the B subunit. Our data suggest that these two distinct sites could cooperate in the reconstituted enzyme.

Simocyclinone D8 turns on against Gram-negative bacteria in a clinical setting

2010 ◽  
Vol 20 (3) ◽  
pp. 1202-1204 ◽  
Author(s):  
Sara N. Richter ◽  
Ilaria Frasson ◽  
Manlio Palumbo ◽  
Claudia Sissi ◽  
Giorgio Palù
Keyword(s):  
Clinical Setting ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Simocyclinone D8

ChemInform Abstract: Biosynthesis of Simocyclinone D8 in an 18O2-Rich Atmosphere.

ChemInform ◽  
2010 ◽  
Vol 33 (32) ◽  
pp. no-no
Author(s):  
Meike Holzenkaempfer ◽  
Axel Zeeck
Keyword(s):  
Simocyclinone D8

scholarly journals Biosynthetic Gene Cluster of Simocyclinone, a Natural Multihybrid Antibiotic

2002 ◽  
Vol 46 (5) ◽  
pp. 1174-1182 ◽  
Author(s):  
A. Trefzer ◽  
S. Pelzer ◽  
J. Schimana ◽  
S. Stockert ◽  
C. Bihlmaier ◽  
...  
Keyword(s):  
Gene Cluster ◽  
High Performance ◽  
Biosynthetic Gene Cluster ◽  
Open Reading Frames ◽  
Primary Metabolites ◽  
Streptomyces Antibioticus ◽  
Mutant Strains ◽  
In The Wild ◽  
Simocyclinone D8 ◽  
Reading Frames

ABSTRACT The entire simocyclinone biosynthetic cluster (sim gene cluster) from the producer Streptomyces antibioticus Tü6040 was identified on six overlapping cosmids (1N1, 5J10, 2L16, 2P6, 4G22, and 1K3). In total, 80.7 kb of DNA from these cosmids was sequenced, and the analysis revealed 49 complete open reading frames (ORFs). These ORFs include genes responsible for the formation and attachment of four different moieties originating from at least three different pools of primary metabolites. Also in the sim gene cluster, four ORFs were detected that resemble putative regulatory and export functions. Based on the putative function of the gene products, a model for simocyclinone D8 biosynthesis was proposed. Biosynthetic mutants were generated by insertional gene inactivation experiments, and culture extracts of these mutants were analyzed by high-performance liquid chromatography. Production of simocyclinone D8 was clearly detectable in the wild-type strain but was not detectable in the mutant strains. This indicated that indeed the sim gene cluster had been cloned.

scholarly journals SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors

AMB Express ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 1 ◽  
Author(s):  
Liliya Horbal ◽  
Yuriy Rebets ◽  
Mariya Rabyk ◽  
Roman Makitrynskyy ◽  
Andriy Luzhetskyy ◽  
...  
Keyword(s):  
Simocyclinone D8
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