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De la genèse d’une nouvelle classe d’antibactériens à base de polyphénols cycliques de type calixarène : études moléculaire(s), cellulaires(s) et structurale(s) en vue de l'identification des cibles d'action : le cas du para-guanidinoéthylcalix[4]arène

Abstract : The progressive reduction of the therapeutic effectiveness of the available antibiotics and antiseptics as a result of the spread of antimicrobial resistance underlines the urgency of the development of new classes of drugs for the treatment of infectious diseases. The major challenge is to find drugs that act against multiple multidrug-resistant strains, with a real new mechanism of action. The work presented here is an evaluation of the potential of the para-guanidinoethylcalix[4]arene (Cx1), as a new innovative antibacterial. In the first part of this work, we have demonstrated that Cx1 possess: (i) a broad-spectrum with an activity conserved against multidrug-resistant isolates such as MRSA, VRE or ESBL-producing Enterobacteriaceae; (ii) a rapid bactericidal and concentration-dependant activity; and (iii) an absence of cytotoxicity in vitro. Checkerboard studies have underlined a large number of synergies with numerous antibiotics (ß-lactamins, fluoroquinolones, rifampicin, fusidic acid, tigecycline…) ; no antagonism have been observed. In the second part, we have showed that Cx1 was not able to select resistant mutants with S. aureus and P. aeruginosa. For E. coli, we have observed resistant mutants beyond 15 or 20 passages, with inoculums effect. In the last part of this work, we have used various techniques in order to elucidate mechanism of action of Cx1: innovative techniques (microelectrophoresis, atomic force microscopy),and other more classical (flow cytometry, LPS/LTA sequestration). All data obtained conduct us to confirm our first hypothesis: Cx1 possess one or many targets on bacterial cell wall, and its activity was translated by wall changes (surface charge density, hydrodynamic properties, membrane permeability), and increase of bacterial rigidity (increase of turgor pressure). In conclusion, Cx1 appears as a good candidate as new antibacterial or adjuvant in anti-infectious therapy, but its real mechanism of action remains unknown. Numerous research ways remain to be investigated in order to better understand of targets of Cx1, and to optimize its antibacterial properties.
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Marion Grare. De la genèse d’une nouvelle classe d’antibactériens à base de polyphénols cycliques de type calixarène : études moléculaire(s), cellulaires(s) et structurale(s) en vue de l'identification des cibles d'action : le cas du para-guanidinoéthylcalix[4]arène. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10138⟩. ⟨tel-01746315⟩

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