期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 24, 页码 16234-16251出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00766
关键词
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The discovery and rapid spread of NDM-1, along with the presence of clinically relevant VIM-1 and IMP-1, highlighted the importance of finding pan inhibitors targeting metallo-beta-lactamases (MBLs) in the fight against bacterial infections. By performing fragment and high-throughput screenings, as well as a knowledge-based search, researchers identified compound 12 with activity against NDM-1 only. Through structure-guided optimization, a series of compounds represented by 23 with a pan MBL inhibition profile was discovered, with 23 showing potential as a clinical candidate for MBLIs.
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.
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