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Development of New Drugs for an Old Target — The Penicillin Binding Proteins
Centre de Recherches du Cyclotron, B30, Université de Liège, Sart-Tilman, B-4000 Liège, Belgium
Centre d'Ingénerie des Protéines, Institut de Chimie, B6a, Université de Liège, Sart-Tilman, B-4000 Liège, Belgium
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 13 September 2012; in revised form: 5 October 2012 / Accepted: 17 October 2012 / Published: 24 October 2012
Abstract: The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs). PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics.
Keywords: non-β-lactam; penicillin binding protein; β-lactam resistance; transition state analogs; substrate analogs; inhibitors
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Zervosen, A.; Sauvage, E.; Frère, J.-M.; Charlier, P.; Luxen, A. Development of New Drugs for an Old Target — The Penicillin Binding Proteins. Molecules 2012, 17, 12478-12505.
Zervosen A, Sauvage E, Frère J-M, Charlier P, Luxen A. Development of New Drugs for an Old Target — The Penicillin Binding Proteins. Molecules. 2012; 17(11):12478-12505.
Zervosen, Astrid; Sauvage, Eric; Frère, Jean-Marie; Charlier, Paulette; Luxen, André. 2012. "Development of New Drugs for an Old Target — The Penicillin Binding Proteins." Molecules 17, no. 11: 12478-12505.