[en] The straightforward synthesis of aminoribosyl uridines substituted by a 5'-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the 5' position by an aminomethyl group. This common intermediate resulted from the diastereoselective glycosylation of a phthalimido uridine derivative with a ribosyl fluoride as a ribosyl donor. The inhibition of the MraY transferase activity by the synthetized 11 urea-containing inhibitors was evaluated and 10 compounds revealed MraY inhibition with IC50 ranging from 1.9 μM to 16.7 μM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative bacteria. Four compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 μg mL-1, including methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Interestingly, one compound also revealed antibacterial activity against Pseudomonas aeruginosa with MIC equal to 64 μg mL-1. Docking experiments predicted two modes of positioning of the active compounds urea chain in different hydrophobic areas (HS2 and HS4) within the MraY active site from Aquifex aeolicus. However, molecular dynamics simulations showed that the urea chain adopts a binding mode similar to that observed in structural model and targets the hydrophobic area HS2.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Oliver, Martin ; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Le Corre, Laurent; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Poinsot, Mélanie; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Corio, Alessandra; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Madegard, Léa; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Bosco, Michaël ; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Amoroso, Ana Maria ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Joris, Bernard ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Auger, Rodolphe; Institute for Integrative Biology of the Cell (I2BC), CNRS, Université Paris Sud, CEA, F-91405, Orsay, France
Touzé, Thierry; Institute for Integrative Biology of the Cell (I2BC), CNRS, Université Paris Sud, CEA, F-91405, Orsay, France
Bouhss, Ahmed; Laboratoire Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Univ Evry, INSERM U1204, Université Paris-Saclay, 91025 Evry, France
Calvet-Vitale, Sandrine ; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
Gravier-Pelletier, Christine ; Université de Paris, Faculté des Sciences, UMR CNRS 8601, LCBPT, F-75006 Paris, France. christine.gravier-pelletier@u-paris.fr sandrine.calvet-vitale@u-paris.fr
CNRS - Centre National de la Recherche Scientifique MESR - France. Ministère de l'Enseignement supérieur et de la Recherche
Funding text :
We thank the “Centre National de la Recherche Scientifique” and the Ministère de l’Enseignement Supérieur et de la Recherche for financial support of this work and for M. O. PhD grant. We warmly thank Dr D. Padovani (CNRS UMR 8601) for his interest in this work and for helpful discussion. This work has benefited from the facilities and expertise of the Small Molecule Mass Spectrometry platform of IMAGIF (Centre de Recherche de Gif – http://www.imagif.cnrs.fr). The assistance of P. Gerardo (Université de Paris) for low resolution and high resolution mass spectra analyses is gratefully acknowledged. We acknowledge the Macromolecular Modelling Platform and the NMR platform core facilities of the BioTechMed facilities INSERM US36|CNRS UMS2009| Université de Paris for docking and MD simulation and NMR experiments, respectively.We thank the ?Centre National de la Recherche Scientifique? and the Minist?re de l'Enseignement Sup?rieur et de la Recherche for financial support of this work and for M. O. PhD grant. We warmly thank Dr D. Padovani (CNRS UMR 8601) for his interest in this work and for helpful discussion. This work has benefited from the facilities and expertise of the Small Molecule Mass Spectrometry platform of IMAGIF (Centre de Recherche de Gif. The assistance of P. Gerardo (Universit? de Paris) for low resolution and high resolution mass spectra analyses is gratefully acknowledged. We acknowledge the Macromolecular Modelling Platform and the NMR platform core facilities of the BioTechMed facilities INSERM US36|CNRS UMS2009|Universit? de Paris for docking and MD simulation and NMR experiments, respectively.
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