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Rôle de la sous-unité sigma de l'ARN polymérase bactérienne dans la tolérance aux antibiotiques

Abstract : The RNA polymerase (RNAP) is the central enzyme for genes expression. All forms of life own RNAP. It is a multi-protein complex composed of several subunits responsible of the process of the transcription. The prokaryotes have only one type of RNAP responsible of synthesis of all RNAs in the cells, whereas eukaryotes have three types of RNAPs for the synthesis of the various types of RNAs.RNAP is the target of a large number of proteins and small regulatory molecules including antibiotics used the treatment of various infectious diseases. The sigma subunit of the bacterial RNAP is implicated in all steps of transcription initiation which is the crucial point of genes expression.For example some of the sigma subunits activate genes of virulence in pathogenic bacteria and are implied in the persistence which is a form of survival to the antibiotic treatments.This project aimed to explore the role of the sigma subunits of RNAP bacterial polymerase in resistance to the lipiarmycine (Fidaxomicin). We used biochemical approaches, biophysics and genetics for the study of the dynamic of the interactions DNA-protein in the complexes formed by RNA polymerase, the antibiotic and the promoter DNA. The results of our study show that sensitivity of RNAP to the drug strongly depends on the structure of the sigma region 3.2 and that the regions 1.2 and 3.2 of the sigma subunit are implied in the formation of the RNAP-promoter open complex. Mutations in these regions allosterically affected action of lipiarmycin by impairing the formation of the open complex.These results suggest that conformation and mobility of the region 3.2 depend on its sequence. The outcomes of our work could be used for development of new more effective drugs and could help to progress the studies of the fundamental mechanisms of the transcription.
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Zakia Benabad. Rôle de la sous-unité sigma de l'ARN polymérase bactérienne dans la tolérance aux antibiotiques. Médecine humaine et pathologie. Université Montpellier, 2016. Français. ⟨NNT : 2016MONTT064⟩. ⟨tel-01557507⟩

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