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Master Thesis

Lutte contre l’antibiorésistance : intérêt des oligonucleotides modifiés chez les entérobactéries productrices de béta-lactamases à spectre étendu

Abstract : Extended-spectrum β-lactamases (ESBL)-producing Enterobacteriaceae (such as Escherichia coli) are categorized as critical priority pathogens by the World Health Organization. Indeed, they produce enzymes, mainly CTX-M-15 type, whose genes were acquired by plasmids, which hydrolyze most of β-lactams such as third generation cephalosporins (3GC) widely used to treat infection, which lead to therapeutic impasses. In addition to promoting the rational use of antibiotics and prevention of transmission of multidrug-resistant bacteria, the research of new therapeutic strategies is necessary and encouraged to tackling antibiotic resistance. This work concerns the study of nucleolipid-conjugated oligonucleotides (LON) in combination with ceftriaxone (3GC), on resistant strains of E. coli carrying CTX-M-15 type ESBL. We show that LONs decrease the minimum inhibitory concentration of ceftriaxone up to 26-fold in a dose-dependent manner. This effect is due to the lipid moiety, which improve cellular uptake of the oligonucleotide; a phosphorothioate chemistry and an adequate number of nucleotides. In the absence of ceftriaxone, LONs do not affect bacterial growth. Their mechanism of action has been studied by RT- qPCR and Western Blot experiments and by monitoring the hydrolysis of nitrocefine, a chromogenic cephalosporin. Thus LONs do not decrease the amount of RNA and β-lactamase CTX-M- 15 protein but decrease its enzymatic activity. LONs are potential new strategy for tackling antibiotic resistance and their application could be extended to other bacteria, antibiotics and resistances.
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Master Thesis
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Submitted on : Monday, September 14, 2020 - 3:56:59 PM
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Léa Bientz. Lutte contre l’antibiorésistance : intérêt des oligonucleotides modifiés chez les entérobactéries productrices de béta-lactamases à spectre étendu. Sciences du Vivant [q-bio]. 2020. ⟨dumas-02937996⟩

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