Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E

Hiroaki Itoh, Kotaro Tokumoto, Takuya Kaji, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu and Masayuki Inoue ()
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Hiroaki Itoh: The University of Tokyo
Kotaro Tokumoto: The University of Tokyo
Takuya Kaji: The University of Tokyo
Atmika Paudel: Teikyo University Institute of Medical Mycology
Suresh Panthee: Teikyo University Institute of Medical Mycology
Hiroshi Hamamoto: Teikyo University Institute of Medical Mycology
Kazuhisa Sekimizu: Teikyo University Institute of Medical Mycology
Masayuki Inoue: The University of Tokyo

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10754-4

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