Abstract:
:Lysocin E, a 37-membered natural depsipeptide, induces rapid bacteriolysis in methicillin-resistant Staphylococcus aureus via a unique menaquinone-dependent mechanism, presenting a promising therapeutic lead. Despite the great medical importance, exploring the potential utility of its derivatives as new platform structures for antibiotic development has remained a significant challenge. Here, we report a high-throughput strategy that enabled the preparation of thousands of analogues of lysocin E and large-scale structure-activity relationship analyses. We integrate 26-step total synthesis of 2401 cyclic peptides, tandem mass spectrometry-sequencing, and two microscale activity assays to identify 23 candidate compounds. Re-synthesis of these candidates shows that 11 of them (A1-A11) exhibit antimicrobial activity superior or comparable to that of lysocin E, and that lysocin E and A1-A11 share L-Leu-6 and L-Ile-11. Therefore, the present strategy allows us to efficiently decipher biologically crucial residues and identify potentially useful agents for the treatment of infectious diseases.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Itoh H,Tokumoto K,Kaji T,Paudel A,Panthee S,Hamamoto H,Sekimizu K,Inoue Mdoi
10.1038/s41467-019-10754-4subject
Has Abstractpub_date
2019-07-05 00:00:00pages
2992issue
1issn
2041-1723pii
10.1038/s41467-019-10754-4journal_volume
10pub_type
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