Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

Yuri Takada, Hiroaki Itoh, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu and Masayuki Inoue ()
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Yuri Takada: The University of Tokyo
Hiroaki Itoh: 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, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.

Date: 2020
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DOI: 10.1038/s41467-020-18711-2

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