Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1.
The emergence of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health problem. Recently, we found amino acid thioesters to be a highly promising scaffold for inhibitors of the MβL L1. In order to optimize this series of inhibitors, nine new amino acid thioesters were developed by modifying the substituents on the N-terminus of the thioesters and the groups representing the amino acid side chain. Biological activity assays indicate that all of them are very potent inhibitors of L1 with an IC50 value range of 20-600nM, lower than those of most of the previously reported inhibitors of this scaffold. Analysis of structure-activity relationship reveals that big hydrophobic substituents on the N-terminus and a methionine amino acid side chain improves inhibitory activity of the thioesters. All these inhibitors are able to restore antibacterial activity of a β-lactam antibiotic against Escherichia coli BL21(DE3) cells producing L1 to that against E. coli cells lacking a β-lactamase. Docking studies reveal that a large N-terminal hydrophobic group results in a slightly different binding mode than smaller hydrophobic groups at the same position.
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Xiao-Long
XL
Liu
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Ke-Wu
KW
Yang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Yue-Juan
YJ
Zhang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Ying
Y
Ge
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Yang
Y
Xiang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Lab, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Ya-Nan
YN
Chang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.
Peter
P
Oelschlaeger
D000596:Amino Acids / Q000737:chemistry*; D004952:Esters; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000187:drug effects*
D000596:Amino Acids; D004952:Esters; D065093:beta-Lactamase Inhibitors; C088032:beta-lactamase L1; D001618:beta-Lactamases
Antibiotic resistance; Inhibitor; L1; Mercaptoacetic acid thioester; Metallo-β-lactamase