67 research outputs found
A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase
Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets
The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding
SimR, a TetR-family transcriptional regulator (TFR), controls the export of simocyclinone, a potent DNA gyrase inhibitor made by Streptomyces antibioticus. Simocyclinone is exported by a specific efflux pump, SimX and the transcription of simX is repressed by SimR, which binds to two operators in the simR-simX intergenic region. The DNA-binding domain of SimR has a classical helix-turn-helix motif, but it also carries an arginine-rich N-terminal extension. Previous structural studies showed that the N-terminal extension is disordered in the absence of DNA. Here, we show that the N-terminal extension is sensitive to protease cleavage, but becomes protease resistant upon binding DNA. We demonstrate by deletion analysis that the extension contributes to DNA binding, and describe the crystal structure of SimR bound to its operator sequence, revealing that the N-terminal extension binds in the minor groove. In addition, SimR makes a number of sequence-specific contacts to the major groove via its helix-turn-helix motif. Bioinformatic analysis shows that an N-terminal extension rich in positively charged residues is a feature of the majority of TFRs. Comparison of the SimRâDNA and SimRâsimocyclinone complexes reveals that the conformational changes associated with ligand-mediated derepression result primarily from rigid-body rotation of the subunits about the dimer interface
Exploiting bacterial DNA gyrase as a drug target: current state and perspectives
DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme
Om du vill ha fred, förbered dig pÄ krig : en studie i den militÀra styrkans betydelse
Denna uppsats kretsar kring att pröva hur en av de frÀmsta företrÀdarna för den realistiska skolan, förklarar de amerikanska anfallen mot Afghanistan (2001) och Irak (2003). Hans namn Àr Robert Kagan och uppsatsen syftar till ge en realists tolkning till varför USA handlade som man gjorde. Man mÄste dÀrför försöka uppfatta vÀrlden utifrÄn USA:s horisont och försöka tolka samt sÀtta sig in i den amerikanska positionen pÄ den internationella arenan. Problemformuleringarna kretsar kring att fÄ insikt i grundstenarna i Kagans teori, samt hur Kagans grundsyn skiljer sig gentemot den idealistiska. Vidare hur USA:s militÀra styrka, enligt Kagan, pÄverkar dess beteende pÄ den internationella arenan, men Àven hur Kagan ser pÄ USA:s kommande globala engagemang. Robert Kagans bok Om paradiset och makten USA och Europa i den nya vÀrldsordningen kommer att utgöra fundamentet i studien. I boken kretsar bl.a. Kagans resonemang kring att USA och Europa distanserar frÄn varandra, men Àven kring militÀr styrka. DÀrför ger boken oss en vÀldigt bra bild av USA:s position pÄ den internationella arenan. Kagans resonemang vÀvs sedan ihop med kritik, realism, idealism och geopolitik. Slutsatsen blir att grundstenarna i Kagans resonemang Äterfinns i den s.k. realismteorin, men Àven till viss del i geopolitiken. Han sÀtter stor vikt vid militÀra medel och ser staterna som de mest betydelsefulla aktörerna, samt ser vÀrlden som allmÀnt hotfull. Han realistiska resonemang grundas pÄ amerikanska spelregler och ledarskap pÄ den internationella arenan. Skillnaden mellan Kagans grundsyn och den idealistiska bottnar frÀmst i idealisternas fokusering pÄ integration mellan stater. Vidare att de sÀtter tilltro till internationell rÀtt, samt har ett mer multilateralt förhÄllningssÀtt till omvÀrlden. Kagan menar vidare att starka stater Àr mer villiga att anvÀnda tvÄng och hot i internationella relationer. De bedömer dessutom hot och risker annorlunda jÀmfört med svagare stater. Enligt Kagan beter sig USA som en internationell sheriff pÄ den globala arenan och beteendet bottnar i militÀr styrka. Vidare anser Kagan att USA har haft samma kurs i flera Ärhundraden. USA har expanderat in i Europa och Asien och aldrig dragit sig tillbaka. Man hade redan före den 11 september 2001 fokuserat pÄ Kina som motspelare. Dessutom, menar Kagan, att USA varit villiga att satsa pÄ ny militÀr teknik, vilken kan förÀndra krigföringen. Han skriver Àven att bÄde Clinton och Bushadministrationen varit grundade pÄ att USA Àr en nödvÀndig nation, samt att amerikaner vill beskydda och sprida det liberala systemet i vÀrlden
ChemInform Abstract: Arylomycins A and B, New Biaryl-Bridged Lipopeptide Antibiotics Produced by Streptomyces sp. Tue 6075. Part 1. Taxonomy, Fermentation, Isolation and Biological Activities.
ChemInform Abstract: Simocyclinones, Novel Cytostatic Angucyclinone Antibiotics Produced by Streptomyces antibioticus Tue 6040. Part 1. Taxonomy, Fermentation, Isolation, and Biological Activities.
Capacity of health-care facilities to deliver HIV treatment and care services, Northern Tanzania, 2004.
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49877.pdf (publisher's version ) (Closed access)Few data exist on the current capacity of Tanzanian health-care facilities to deliver antiretroviral therapy (ART). We evaluated this capacity among Northern Zone facilities in 2004 using a questionnaire that addressed human resources, clinical facilities and services, and laboratory capacity. Of 19 facilities surveyed, nine (47%) had staff trained to manage ART and three (16%) prescribed ART. Two (11%) offered CD4 counts, five (26%) offered liver function tests, 16 (84%) offered chest radiography, and 18 (95%) offered acid-fast sputum staining. Of 12 (67%) facilities offering outpatient HIV/AIDS services, 12 (100%) provided co-trimoxazole to outpatients and six (50%) provided isoniazid (INH). All 19 (100%) facilities offered rapid HIV tests and full blood pictures. Overall in 2004, facilities needed strengthening to increase staff training in ART management and to implement INH for treatment of latent tuberculosis. Laboratory facilities for ART monitoring were inadequate, and outpatient ART was limited
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