A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance

Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA (‘poisoning’) in an analogous fashion to fluoroquinolones, but without the requirement for the water–metal–ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase–DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development

Influence of Fluorination at Position 16 of Antibacterial Pristinamycins II#

The influence of a fluorine atom at position C(16) of antibacterial pristinamycins II upon antibacterial, physico-chemical and pharmacokinetics properties is described

Mixité sociale, et après ?

International audienceAu cœur des débats publics actuels sur les modalités d’existence et de fonctionnement d’une communauté de citoyens se trouvent les questions urbaine et territoriale. Les « ghettos » sont ainsi opposés à un idéal de mixité sociale. Mais le succès des discours en faveur de cet idéal occulte le fait que la mixité peut servir des valeurs et des intérêts très divers. Cet ouvrage souligne la complexité des processus en cause et déconstruit plusieurs idées reçues. Il éclaire les enjeux de la ville d’aujourd’hui pour dépasser la binarité de façade entre un « apartheid » dont on connaît les méfaits et des politiques de mixité sociale dont on surestime les avantages. En s’appuyant sur les recherches urbaines les plus récentes, les auteurs discutent les effets de dynamiques actuelles telles que la gentrification, la périurbanisation ou la ségrégation

A concise synthesis of the tricyclic skeleton of pleuromutilin and a new approach to cycloheptenes

International audience(Matrix presented) A short synthesis of the tricyclic skeleton of pleuromutilin is reported, featuring an unusually efficient 8-endo-trig radical cyclization of a xanthate precursor. In the course of this study, a one-carbon ring expansion leading to cycloheptenes was uncovered

The Middle Class "at Home among the Poor" - How Social Mix Is Lived in Parisian Suburbs: Between Local Attachment and Metropolitan Practices

International audienceHow do households belonging to the middle classes decide to come live in a `poor' city in the Parisian suburbs? What makes them stay? What are the judgements and strategies that have been brought to bear both individually in their daily lives and as a social group in terms of their collective involvement and their relationships with other social groups? What does this kind of `social mix' imply in terms of social practices, local and social belonging? This article shows that attitudes towards social mixing have to be considered in terms of their sociological dimensions. This analysis thus takes into account middle-class diversity in socio-residential terms, in terms of trajectories, values and attachment to a particular area. The article also emphasizes the importance of distinguishing between different dimensions of attitudes towards social mixing: depending on the issues at stake, people can accept and sometimes promote a form of cohabitation, or, quite to the contrary, reject it. Finally, the article emphasizes the importance of local contexts and their temporality: for someone belonging to the middle classes, living in a poor city may also mean holding a relatively higher position than elsewhere

Tin-free radical cyclizations for the synthesis of 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b] azepin-8-ones

International audience(Chemical Equation Presented) Compounds containing a pyridine nucleus fused to a saturated nitrogen-containing ring, including 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b] azepin-8-ones, were prepared in good yield starting from various 2,6-dichloropyridines. The method hinges on a free-radical xanthate-mediated cyclization or intermolecular addition/cyclization sequence for the construction of the new fused rings

Influence of steric crowding on the electrochemical reduction of substituted tertiary pyridylcarboxamides in aqueous acidic medium

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Incidence of the peptidic lactone opening on the electrochemical reduction of pristinamycin IA

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