期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 15, 页码 10890-10899出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00176
关键词
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资金
- European Research Council (ERC) [725523]
- European Research Council (ERC) [725523] Funding Source: European Research Council (ERC)
The escalating antibiotic resistance, especially among Gram-negative pathogens, calls for novel antibiotics targeting unexploited bacterial targets. Recent studies have shown that combining OMP-targeting macrocyclic peptides with PMEN enhances their antibacterial activity, effectively combating a range of Gram-negative pathogens, including multi-drug-resistant isolates.
The continuing rise of antibiotic resistance, particularly among Gram-negative pathogens, threatens to undermine many aspects of modern medical practice. To address this threat, novel antibiotics that utilize unexploited bacterial targets are urgently needed. Over the past decade, a number of studies have highlighted the antibacterial potential of macrocyclic peptides that target Gram-negative outer membrane proteins (OMPs). Recently, it was reported that the antibacterial activities of OMP-targeting macrocyclic peptidomimetics of the antimicrobial peptide protegrin-1 are dramatically enhanced upon linking to polymyxin E nonapeptide (PMEN). In this study, we describe a convergent, chemoenzymatic route for the convenient preparation of such conjugates. Specifically, we investigated the use of both amide bond formation and azide-alkyne ligation for connecting an OMP-targeting macrocyclic peptide to a PMEN building block (obtained by enzymatic degradation of polymyxin E). The conjugates obtained via both approaches display potent antibacterial activity against a range of Gram-negative pathogens including multi-drug-resistant isolates.
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