As an opponent to the renowned bicyclic β-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, we designed a new class of potential monocyclic β-lactam-containing inhibitors of penicillin-binding proteins using in silico ligand- and structure-based drug design methods. A virtual combinatorial library of functionalized monocyclic 3-amino-β-lactams was generated, after which a virtual screening campaign was performed based on two powerful fifth-generation cephalosporins, ceftaroline and ceftobiprole. The highest scoring hits, based on electronic and sterical similarity with the pharmacophore model, were selected for a covalent docking analysis using crystal data of PBP5fm of Enterococcus faecium. The resulting β-lactams have in common that they reveal the preference for a side chain (‘R’) embedding a lipophilic linker and a terminal hydrogen bond-donating or -accepting functionality (‘HBD/HBA’), enabling additional non-covalent interactions with the key residues in the enzyme’s active site. In a next stage, targeting high-scoring compounds from the drug design protocol, visually selected for synthetic feasibility, a ten-step synthesis of functionalized enantiomerically pure 4-unsubstituted 3-acetamido-1-carboxymethyl-β-lactams was elaborated starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-β-lactams to inhibit various resistant penicillin-binding proteins was assessed in vitro, unravelling their potential as lead structures in the pursuit of novel potent PBP inhibitors.

Targeting bacterial drug resistance: Design, synthesis and evaluation of monocyclic 3-amino-1-carboxymethyl-β-lactams as potential inhibitors of Penicillin-binding proteins

255th National Meeting (2018)

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