Disease relevance of COUMERMYCIN

• Nalidixic acid, novobiocin and coumermycin specifically inhibit phage promoter-dependent transcription of the trp operon in phi 80 ptrp but not transcription from the authentic trp promoter [1].
• Novobiocin and coumermycin are known to inhibit the replication of DNA iing of DNA catalyzed by E. coli DNA gyrase, a recently discovered enzyme that introduces negative superhelical turns into covalently circular DNA [2].
• In vivo transcription by the N4 virion RNA polymerase is inhibited by coumermycin [3].
• Both novobiocin and coumermycin alter the susceptibility of vaccinia topoisomerase to proteolysis with either chymotrypsin or trypsin; similar effects occur when topoisomerase binds to duplex DNA [4].
• Herpes simplex virus cloned DNA fragments induce coumermycin A1 resistance in Escherichia coli [5].

High impact information on COUMERMYCIN

• Coumermycin, a potent inhibitor of DNA gyrase subunit B, inhibits transposition in a wild-type strain, but has no effect on strains carrying a coumermycin-resistant allele in gyrB [6].
• Similar relaxation occurs when cells are treated with the DNA gyrase inhibitor coumermycin [7].
• To investigate the mechanisms underlying Raf activation, we have developed a coumermycin-induced chemical dimerization method [8].
• Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization [8].
• Coumermycin- induced L-selectin dimerization resulted in an approximately fourfold increase in binding of phosphomanan monoester core complex (PPME), a natural mimic of an L-selectin ligand, comparable to that observed after leukocyte activation [9].

Chemical compound and disease context of COUMERMYCIN

• The fluoroquinolone enrofloxacin inhibits DNA relaxation by Vaccinia topoisomerase I at concentrations similar to those required for inhibition by the coumarin drugs coumermycin and novobiocin [10].
• All Campylobacter species were resistant to novobiocin (MIC, 32 to 512 micrograms/ml), but most strains were susceptible to the other DNA gyrase subunit B inhibitors coumermycin A1 and clorobiocin [11].
• Treatment of Staphylococcus aureus endocarditis in rats with coumermycin A1 and ciprofloxacin, alone or in combination [12].
• The susceptibility of 10 multiply antibiotic-resistant strains of Streptococcus pneumoniae to several quinoline antibiotics and to coumermycin, novobiocin, and penicillin was determined [13].
• The biosynthetic gene cluster of the aminocoumarin antibiotic coumermycin A(1) was cloned by screening of a cosmid library of Streptomyces rishiriensis DSM 40489 with heterologous probes from a dTDP-glucose 4,6-dehydratase gene, involved in deoxysugar biosynthesis, and from the aminocoumarin resistance gyrase gene gyrB(r) [14].

Biological context of COUMERMYCIN

• Finally, coumermycin-mediated dimerization of a GyrB-KD fusion protein increased eIF2alpha phosphorylation and inhibited reporter gene translation in mammalian cells [15].
• Since homologous mutant gyrB (coumermycin resistant) truncated genes did not confer drug resistance at all under the same conditions, we propose that this mechanism of resistance is due to drug sequestration by the overproduced wild-type GyrB polypeptides [16].
• The ability to activate the entire Raf signal transduction cascade conditionally, using coumermycin-induced oligomerization, should prove useful for dissecting Raf-mediated effects on gene expression and cellular differentiation [17].
• Spectroscopic and fluorescence measurements of drug binding t enzyme indicate a single binding site on vaccinia topoisomerase for coumermycin (KD = 27 +/- 5 microM) and two classes of binding sites for novobiocin, one tight site (KD1 = 20 +/- 5 microM) and several weak sites (KD2 = 513 +/- 125 microM; n = 4.9 +/- 0.7) [4].
• To investigate the specific role of Jak2 in the regulation of signal transduction pathways, we generated gyrase B (GyrB)-Jak2 fusion proteins, dimerized through the addition of coumermycin [18].

Anatomical context of COUMERMYCIN

• The modified Tyk2 was activated in a coumermycin-dependent manner, and the activated Tyk2 conferred cytokine independence upon interleukin-3-dependent pro-B lymphoid cells [19].
• When expressed in porcine aortic endothelial cells, both chimeric VEGFR-1 and -2 autophosphorylate in response to addition of the small-molecule dimerizing agent, coumermycin [20].
• Novobiocin and coumermycin A1 inhibit viral replication and the reactivation of herpes simplex virus type 1 from the trigeminal ganglia of latently infected mice [21].
• Coumermycin, an inhibitor of DNA-gyrase, was highly concentrated (11.3 to 16.6-fold) within the neutrophils [22].
• Coumermycin inhibition of murine retrovirus replication in cultured cells [23].

Associations of COUMERMYCIN with other chemical compounds

• The subunits can be identified as the products of two genes, determining resistance to coumermycin A1 and novobiocin (cou) and to nalidixic acid and oxolinic acid (nalA), respectively [24].
• The stimulation is abolished by coumermycin A1 and is not found in extracts of nalidixic acid-resistant (gyrA) mutants [25].
• The mutants can grow only at temperatures below 34 degrees C-35 degrees C. Heat, ethanol, and coumermycin induce major heat shock proteins in the wild-type but not in the htpR mutants [26].
• SyrC joins a growing family of such aminoacyl-shuttling enzymes that also use covalent catalysis to move aminoacyl groups from carrier proteins during coumermycin and coronamic acid biosynthesis [27].
• NAD, pyridoxal phosphate, and coumermycin A1, which exhibit no antiviral activity but are typically used to probe nucleotide binding sites, were also tested [28].

Gene context of COUMERMYCIN

• Dimerization of Stat3-GyrB by coumermycin mimicked the effect of IL-10, and expression of DeltaStat3 blocked the anti-proliferative activity of IL-10 [29].
• Coumermycin induced autophosphorylation of GyrB-Jak2 fusion proteins, thus bypassing receptor activation [18].
• To investigate the specific role of dimerization in the internalization process of GPCRs, we generated a fusion protein of hPAFR and bacterial DNA gyrase B (GyrB), dimerized through the addition of coumermycin [30].
• To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin [31].
• Not all sites were equally sensitive to oxolinic acid concentration, some sites exhibited an altered cleavage frequency when the gyrB225 delta topA mutant strain DM800 was compared with wild-type cells, and coumermycin selectively changed the cleavage frequency at a few sites in the mutant strain DM800 [32].

Analytical, diagnostic and therapeutic context of COUMERMYCIN

• Site-directed mutagenesis of the lambda repressor-binding domain resulted in significant reduction of basal expression levels and an induction reaching four orders of magnitude in stably transfected 293A cells in response to coumermycin [33].
• In coumermycin assembly, the corresponding ligase CouL makes the bis-amide by tandem ligation of two aminocoumarins to a dicarboxypyrrole [34].
• No interaction between DNA and coumermycin A1 was observed with the following analytical procedures: ultraviolet difference spectra, DNA absorbance-temperature transitions, equilibrium buoyant density centrifugation, and DNA cross-linking determinations [35].
• We have used resistance to the coumarin antibiotic coumermycin A1, an inhibitor of DNA gyrase, as a genetic marker to monitor the transformation of B. burgdorferi by electroporation [36].
• Western blot analysis revealed a 1.4- and 1.5-fold increase in GroEL synthesis following a temperature upshift or by inhibiting DNA supercoiling with coumermycin A1, respectively [37].

References