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Eeyarestatin 24 impairs SecYEG‐dependent protein trafficking and inhibits growth of clinically relevant pathogens
Author(s) -
Steenhuis Maurice,
Koningstein Gregory M.,
Oswald Julia,
Pick Tillman,
O’Keefe Sarah,
Koch HansGeorg,
Cavalié Adolfo,
Whitehead Roger C.,
Swanton Eileithyia,
High Stephen,
Luirink Joen
Publication year - 2021
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.14589
Subject(s) - translocon , biology , endoplasmic reticulum , sec61 , microbiology and biotechnology , transport protein , secretion , mode of action , secretory protein , escherichia coli , membrane protein , biochemistry , gene , membrane
Eeyarestatin 1 (ES1) is an inhibitor of endoplasmic reticulum (ER) associated protein degradation, Sec61‐dependent Ca 2+ homeostasis and protein translocation into the ER. Recently, evidence was presented showing that a smaller analog of ES1, ES24, targets the Sec61‐translocon, and captures it in an open conformation that is translocation‐incompetent. We now show that ES24 impairs protein secretion and membrane protein insertion in Escherichia coli via the homologous SecYEG‐translocon. Transcriptomic analysis suggested that ES24 has a complex mode of action, probably involving multiple targets. Interestingly, ES24 shows antibacterial activity toward clinically relevant strains. Furthermore, the antibacterial activity of ES24 is equivalent to or better than that of nitrofurantoin, a known antibiotic that, although structurally similar to ES24, does not interfere with SecYEG‐dependent protein trafficking. Like nitrofurantoin, we find that ES24 requires activation by the NfsA and NfsB nitroreductases, suggesting that the formation of highly reactive nitroso intermediates is essential for target inactivation in vivo.