title: Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-β-lactamase L1 Inhibitors.
abstract: In light of the biomedical significance of metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2.9 μM and a K i value range of 0.11-0.95 μM using cefazolin as substrate. Partial thioesters also showed effective inhibitory activities against NDM-1 and ImiS with an IC50 value range of 12-96 and 3.6-65 μM, respectively. Also, all these thioesters increased susceptibility of E. coli cells expressing L1 to cefazolin, indicated by a 2-4-fold reduction in MIC of the antibiotic. Docking studies revealed potential binding modes of the two most potent L1 inhibitors to the active site in which the carboxylate group interacts with both Zn(II) ions and Ser221. This work introduces a highly promising scaffold for the development of metallo-β-lactamase L1 inhibitors.
authors.affiliation: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona , 3801 West Temple Avenue, Pomona, California 91768, United States.
authors.forename: Joon S
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences , 309 East Second Street, Pomona, California 91766, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Oelschlaeger
authors.affiliation: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Yang
keywords: Antibiotic resistance; L1; inhibitor; mercaptoacetic acid thioester; metallo-β-lactamase; subclass B3