%AChen, Allie [Department of Chemistry and Biochemistry University of California San Diego La Jolla CA 92093 USA]%AChen, Allie [Department of Chemistry and BiochemistryUniversity of California San Diego La Jolla CA 92093 USA]%AThomas, Pei [Division of Chemical Biology &, Medicinal Chemistry College of Pharmacy University of Texas Austin Austin TX 78712 USA]%AThomas, Pei [Division of Chemical Biology &, Medicinal ChemistryCollege of PharmacyUniversity of Texas Austin Austin TX 78712 USA]%ACheng, Zishuo [Department of Chemistry and Biochemistry Miami University Oxford OH 45056 USA]%ACheng, Zishuo [Department of Chemistry and BiochemistryMiami University Oxford OH 45056 USA]%AXu, Nasa [Division of Chemical Biology &, Medicinal Chemistry College of Pharmacy University of Texas Austin Austin TX 78712 USA]%AXu, Nasa [Division of Chemical Biology &, Medicinal ChemistryCollege of PharmacyUniversity of Texas Austin Austin TX 78712 USA]%ATierney, David [Department of Chemistry and Biochemistry Miami University Oxford OH 45056 USA]%ATierney, David [Department of Chemistry and BiochemistryMiami University Oxford OH 45056 USA]%ACrowder, Michael [Department of Chemistry and Biochemistry Miami University Oxford OH 45056 USA]%ACrowder, Michael [Department of Chemistry and BiochemistryMiami University Oxford OH 45056 USA]%AFast, Walter [Division of Chemical Biology &, Medicinal ChemistryCollege of PharmacyUniversity of Texas Austin Austin TX 78712 USA]%AFast, Walter [Division of Chemical Biology &, Medicinal Chemistry College of Pharmacy University of Texas Austin Austin TX 78712 USA]%ACohen, Seth [Department of Chemistry and Biochemistry University of California San Diego La Jolla CA 92093 USA]%ACohen, Seth [Department of Chemistry and BiochemistryUniversity of California San Diego La Jolla CA 92093 USA]%BJournal Name: ChemMedChem; Journal Volume: 14; Journal Issue: 13; Related Information: CHORUS Timestamp: 2023-09-09 11:33:52 %D2019%IWiley Blackwell (John Wiley & Sons) %JJournal Name: ChemMedChem; Journal Volume: 14; Journal Issue: 13; Related Information: CHORUS Timestamp: 2023-09-09 11:33:52 %K %MOSTI ID: 10103808 %PMedium: X %TInvestigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases %XAbstract

New Delhi metallo‐β‐lactamase‐1 (NDM‐1) poses an immediate threat to our most effective and widely prescribed drugs, the β‐lactam‐containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM‐1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnIIions in the active site of NDM‐1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM‐1 (and related metallo‐β‐lactamases, IMP‐1 and VIM‐2). It was determined that the choice of carboxylate isostere influences both the potency of NDM‐1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal‐stripping mechanism can be re‐engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM‐1 inhibitor design and development.

%0Journal Article