New β-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-β-lactamases.
In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100μM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069, PR China. Electronic address: kwyang@nwu.edu.cn.
Ke-Wu
KW
Yang
Lei
L
Feng
Shao-Kang
SK
Yang
Mahesh
M
Aitha
Alecander E
AE
LaCuran
Peter
P
Oelschlaeger
Michael W
MW
Crowder
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D015780:Carbapenems / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000201:enzymology*; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
Inhibitor; Metallo-β-lactamase; Phospholactam