The 1-β-methyl group confers a lower affinity of l,d-transpeptidase LdtMt2 for ertapenem than for imipenem

Fen Zhao; Yan-Jie Hou; Ying Zhang; Da-Cheng Wang; De-Feng Li

doi:10.1016/j.bbrc.2019.01.082

The 1-β-methyl group confers a lower affinity of l,d-transpeptidase Ldt_Mt2 for ertapenem than for imipenem

Biochem Biophys Res Commun. 2019 Mar 5;510(2):254-260. doi: 10.1016/j.bbrc.2019.01.082. Epub 2019 Jan 25.

Authors

Fen Zhao¹, Yan-Jie Hou², Ying Zhang², Da-Cheng Wang³, De-Feng Li⁴

Affiliations

¹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
³ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: dcwang@ibp.ac.cn.
⁴ University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address: lidefeng@im.ac.cn.

PMID: 30686533
DOI: 10.1016/j.bbrc.2019.01.082

Abstract

L,D-transpeptidases, widely distributed in bacteria and even in the difficult-to-treat ESKAPE pathogens, can confer antibacterial resistance against the traditional β-lactam antibiotics through bypass of the 4 → 3 transpeptide linkage. Ldt_Mt2, a l,d-transpeptidase in Mycobacteria tuberculosis, is essential for bacterial virulence and is considered as a potential anti-tuberculosis target inhibited by carbapenems. Diverse interaction modes between carbapenems and Ldt_Mt2 have been reported, there are only limited evidences to validate those interaction modes. Herein, we identified the stable binding states of two carbapenems, imipenem and ertapenem, via crystallographic and biochemical studies, discovered that they adopt similar binding conformations. We further demonstrate the absence of the 1-β-methyl group in imipenem and the presence of both Y308 and Y318 residues in Ldt_Mt2 synergistically resulted in one order of magnitude higher affinity for imipenem than ertapenem. Our study provides a structural basis for the rational drug design and evolvement of novel carbapenems against bacterial L,D-transpeptidases.

Keywords: Antibacterial drugs; Ertapenem; Imipenem; Ldt(Mt2); Mycobacterium tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry*
Binding Sites
Crystallography, X-Ray
Drug Design
Ertapenem / chemistry*
Imipenem / chemistry*
Kinetics
Mass Spectrometry
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology*
Peptidyl Transferases / chemistry*
Protein Binding
Protein Conformation

Substances

Anti-Bacterial Agents
Imipenem
Peptidyl Transferases
Ertapenem