Journal
FUTURE MEDICINAL CHEMISTRY
Volume 11, Issue 18, Pages 2381-2394Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2019-0008
Keywords
antibacterial resistance; dual functional broad-spectrum inhibitor; metallo-beta-lactamases; synergistic therapy
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Funding
- National Natural Science Foundation of China [81361138018, 21572179]
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Aim: The discovery and development of novel broad-spectrum M beta Ls inhibitors are urgent to overcome antibiotic resistance mediated by M beta Ls. Methods & results: Herein, the synthesized 21 compounds exhibited potent inhibition to the clinically important M beta Ls (NDM-1, IMP-1 and ImiS) and effectively restored the antibacterial efficacy of cefazolin and imipenem against Escherichia coli harboring M beta Ls. 5b was first identified to be dual functional broad-spectrumM beta Ls inhibitor through assemblage of covalent and metal binding scaffold, which irreversibly inhibited B1, B2 M beta Ls via forming a Se-S covalent bond, and competitively inhibited B3 M beta Ls by coordinating the metals at active site. Conclusion: The designed compounds can serve as potent broad-spectrum M beta Ls inhibitors and combat M beta Ls-producing 'superbug' in combination with beta-lactams. [GRAPHICS] The discovery of dual functional broad-spectrum M beta Ls inhibitor through assemblage of covalent and metal binding scaffold.
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