title: Structure-Function Relationships of Class D Carbapenemases.
abstract: Class D carbapenemases, also known as Carbapenem-Hydrolyzing class D β-Lactamases (CHDLs) are of increasingly high clinical relevance, as they have been found in various important human pathogens, such as Acinetobacter baumannii and Klebsiella pneumoniae and contribute to the evolution of these pathogens towards extensively or totally-drug resistance (XDR/TDR) phenotypes. Essentially two main groups of phylogenetically-related enzymes have been described: one including the acquired OXA-23, OXA-24/40, OXA-51 and OXA-58 enzymes mostly in Acinetobacter baumannii, and the other including the OXA-48-related variants, i.e. OXA-54, OXA-162, OXA-163 and OXA- 181. In this article, the biochemical and structural features of class D carbapenemases will be discussed. Furthermore, the mechanistic hypothesis based on recently obtained crystal structures of the native forms of class D carbapenemases and mutants thereof, in complex with relevant substrates or inhibitors, will be critically reviewed. Finally, the mechanism of inhibition by available inhibitors, some of which are currently in clinical development, will be discussed.
authors: Jean-Denis
authors: JD
authors: Docquier
authors: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena, Italy. stefano.mangani@unisi.it.
authors: Stefano
authors: S
authors: Mangani
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010802:Phylogeny; D011487:Protein Conformation; D018440:beta-Lactam Resistance / Q000187:drug effects; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases