title: Diaryl-substituted azolylthioacetamides: Inhibitor discovery of New Delhi metallo-β-lactamase-1 (NDM-1).
abstract: The emergence and spread of antibiotic-resistant pathogens is a global public health problem. Metallo-β-lactamases (MβLs) such as New Delhi MβL-1 (NDM-1) are principle contributors to the emergence of resistance because of their ability to hydrolyze almost all known β-lactam antibiotics including penicillins, cephalosporins, and carbapenems. A clinical inhibitor of MBLs has not yet been found. In this study we developed eighteen new diaryl-substituted azolylthioacetamides and found all of them to be inhibitors of the MβL L1 from Stenotrophomonas maltophilia (Ki < 2 μM), thirteen to be mixed inhibitors of NDM-1 (Ki < 7 μM), and four to be broad-spectrum inhibitors of all four tested MβLs CcrA from Bacteroides fragilis, NDM-1 and ImiS from Aeromonas veronii, and L1 (Ki < 52 μM), which are representative of the B1a, B1b, B2, and B3 subclasses, respectively. Docking studies revealed that the azolylthioacetamides, which have the broadest inhibitory activity, coordinate to the Zn(II) ion(s) preferentially via the triazole moiety, while other moieties interact mostly with the conserved active site residues Lys224 (CcrA, NDM-1, and ImiS) or Ser221 (L1).
authors.affiliation: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, 229 North Taibai Road, Xi'an 7100679 (P.R. China).
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Zhang
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Yang
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Zhou
authors.forename: Alecander E
authors.initials: AE
authors.lastname: LaCuran
authors.forename: Peter
authors.initials: P
authors.lastname: Oelschlaeger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Crowder
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism; D000333:Aeromonas / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001441:Bacteroides fragilis / Q000201:enzymology; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D020615:Stenotrophomonas maltophilia / Q000201:enzymology; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
keywords: NDM-1; antibiotic resistance; antibiotics; inhibitors; metallo-β-lactamases