Diaryl‐Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1) |
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| Authors: | Yi‐Lin Zhang Prof. Ke‐Wu Yang Ya‐Jun Zhou Alecander E. LaCuran Prof. Peter Oelschlaeger Prof. Michael W. Crowder |
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| Affiliation: | 1. 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);2. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766 (USA);3. Department of Chemistry and Biochemistry, Miami University, 160 Hughes Laboratories, Oxford, OH 45056 (USA) |
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| 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 ZnII 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). |
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| Keywords: | antibiotic resistance antibiotics inhibitors metallo‐β ‐lactamases NDM‐1 |
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