A-54556A is a natural acyldepsipeptide (ADEP) antibiotic isolated from the fermentation broth of S. hawaiiensis.¹ Like other ADEP antibiotics, A-54556A binds to the ATP-dependent Clp protease proteolytic subunit ClpP, resulting in constitutive activation of this bacterial protease.^2,3,4 This leads to uncontrolled proteolysis, inhibition of bacterial cell division, and, ultimately, cell death.^1,5 A-54556A preferentially targets Gram-positive bacteria, including staphylococci, streptococci, and enterococci, with minimum inhibitory concentration values in the submicrogram/milliliter range.⁵ ADEP antibiotics are effective against chronic infections as they are able to eradicate chronic biofilm infections, particularly when combined with rifampicin.⁶

≥95%

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1.Brötz-Oesterhelt, H.,Beyer, D.,Kroll, H.P., et al. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nature Medicine 11(10), 1082-1087 (2005).

2.Li, D.H.S.,Chung, Y.S.,Gloyd, M., et al. Acyldepsipeptide antibiotics induce the formation of a structured axial channel in ClpP: A model for the ClpX/ClpA-bound state of ClpP. Chemistry & Biology 17(9), 959-969 (2010).

3.Kirstein, J.,Hoffmann, A.,Lilie, H., et al. The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease. EMBO Mol.Med. 1(1), 37-49 (2009).

4.Fair, R.J. and Tor, Y. Antibiotics and bacterial resistance in the 21^st century. Perspectives in Medicinal Chemistry 6, 25-64 (2014).

5.Sass, P.,Josten, M.,Famulla, K., et al. Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proceedings of the National Academy of Sciences of the United States of America 108(42), 17474-17479 (2014).

6.Conlon, B.P.,Nakayasu, E.S.,Fleck, L.E., et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503(7476), 365-370 (2013).