In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3-Amino-1-carboxymethyl-β-lactams as Inhibitors of Penicillin-Binding Proteins of Resistant Bacteria.
[en] As a complement to the renowned bicyclic β-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten-step synthesis of eleven nocardicin-like enantiomerically pure 2-{3-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-2-oxoazetidin-1-yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-β-lactams to inhibit penicillin-binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α-benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β-lactamase classes was observed, while weak inhibition of class C β-lactamase P99 was demonstrated.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Decuyper, Lena ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Deketelaere, Sari ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Vanparys, Lore; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Jukič, Marko ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
Sosič, Izidor ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
Sauvage, Eric ; Université de Liège - ULiège > Département des sciences de la vie
Amoroso, Ana Maria ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Verlaine, Olivier ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP)
Joris, Bernard ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Gobec, Stanislav ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
D'hooghe, Matthias ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Language :
English
Title :
In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3-Amino-1-carboxymethyl-β-lactams as Inhibitors of Penicillin-Binding Proteins of Resistant Bacteria.
Research Foundation - Flanders the Slovenian Research Agency Belspo IAP
Funding text :
The authors are indebted to the Research Foundation—Flanders (FWO), the Slovenian Research Agency (project L1-6745) and Belspo IAP-Project P44-iPros for financial support. Special thanks are devoted to Asst. Prof. Marija Gencˇić of the University of Nisˇ, Serbia, for the help with the energy-minimization calculations and NOESY experiments and analysis thereof.The authors are indebted to the Research Foundation—Flanders (FWO), the Slovenian Research Agency (project L1-6745) and Belspo IAP-Project P44-iPros for financial support. Special thanks are devoted to Asst. Prof. Marija Genčić of the University of Niš, Serbia, for the help with the energy-minimization calculations and NOESY experiments and analysis thereof.
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