Structures of New Delhi Metallo‐Beta‐Lactamases in Pursuit of New Inhibitors

Abstract

Antibiotic resistance is a cause of ever‐escalating concern throughout the global community. Antibiotics have been essential to the development of modern medicine and its techniques in the past two centuries; however, bacteria have developed mechanisms that have made many antibiotics almost entirely ineffective. Metallo‐Beta‐Lactamases (MBLs) confer resistance to carbapenems, cephalosporins, and penicillins in several clinically relevant Gram‐negative bacteria including Acinetobacter, Pseudomonas aeruginosa, and many Enterobacteriaceae. New Delhi Metallo‐Beta‐lactamases (NDMs) are amongst some of the most worrisome and prevalent MBLs. This family of MBLs is capable of hydrolyzing all generations of bicyclic beta‐lactams. Among this family, NDM‐1, NDM‐4, and NDM‐12 are key members. To combat these proteins, an inhibitor that targets and binds to the enzymes would be needed, preventing them from hydrolyzing antibiotics; however, not enough is known about the structure of the active site, which is crucial in order to develop specific inhibitors that could be used on patients. Herein we describe key differences between the residues in NDM‐1, NDM‐4, and NDM‐12 that alter biochemical activity of each enzyme, and biophysical stability. Together, our crystal structures of these NDM variants, including the first known structure of NDM‐12, biochemical analyses, and biophysical analyses provide a basis for understanding the roles of key residues surrounding the active site within NDM variants. Furthermore, we have determined the structure of NDM‐4 with a novel inhibitor that binds to the zinc ions at the active site. Our studies combine to provide a clearer picture of the biochemical and biophysical properties of New Delhi Metallo‐Beta‐lactamases and how we can exploit these properties to inform drug design efforts to develop new MBL inhibitors.Support or Funding InformationNIH R01GM111926This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.