Characterization of a novel inhibitor for the New Delhi metallo-β-lactamase-4: Implications for drug design and combating bacterial drug resistance

James B Thoden; Bogdan M Benin; Adam Priebe; Woo Shik Shin; Ramaiah Muthyala; Yuk Yin Sham; Hazel M Holden

doi:10.1016/j.jbc.2023.105135

Characterization of a novel inhibitor for the New Delhi metallo-β-lactamase-4: Implications for drug design and combating bacterial drug resistance

J Biol Chem. 2023 Sep;299(9):105135. doi: 10.1016/j.jbc.2023.105135. Epub 2023 Aug 6.

Authors

James B Thoden¹, Bogdan M Benin², Adam Priebe³, Woo Shik Shin², Ramaiah Muthyala⁴, Yuk Yin Sham⁵, Hazel M Holden⁶

Affiliations

¹ Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA.
² Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
³ Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA.
⁴ Department of Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
⁵ Department of Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA; Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: shamx002@umn.edu.
⁶ Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA. Electronic address: Hazel_Holden@biochem.wisc.edu.

Abstract

The bacterial metallo-β-lactamases (MBLs) catalyze the inactivation of β-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2-HPT-6-COOH, was reported as a low cytotoxic nanomolar β-lactamase inhibitor of Verona-integron-encoded metallo-β-lactamase 2, capable of rescuing β-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-β-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6-COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6-COOH and the identification of additional pharmacophores for MBL inhibition.

Keywords: antibiotic resistance; antibiotics; computational biology; crystallography; enzyme kinetics; enzyme structure.

Grants and funding

R35 GM134643/GM/NIGMS NIH HHS/United States