ADEP antibiotics:

Unprecedented target and potent anti-persister activity

Department of Microbial Bioactive Compounds, IMIT

Bacterial resistance to current antibiotics has reached alarming rates and new antibiotic classes with new mechanisms of action are urgently needed. “ADEPs” represent such a new compound class active against a broad spectrum of multi-drug resistant Gram-positive bacteria including Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus sp. (VRE) and Penicillin-resistant Streptococcus pneumonia (PRSP). Treatment with improved ADEP congeners surpassed the marketed antibiotic linezolid in lethal bacterial infections in rodents.

There is high medical need to eradicate bacteria persisting within the human body in a state of dormancy, as they cause recurrent infections and can hardly be cured by any antibiotic available. ADEP is exceptionally active against persister cells of S. aureus and E. faecium and outperformed all marketed antibiotics tested as comparators.

ADEP also stands apart from other antibiotics due to its novel of mode of action; it targets and dysregulates the proteolytic component of the bacterial Clp protease system. ADEP turns this harmless bacterial protease into a deadly weapon. Treated cells “commit suicide” by self-digestion.

Selected publications on ADEP:

Famulla, K., Sass, P., Malik, I., Akopian, T., Kandror, O., Alber, M., Hinzen, B., Ruebsamen-Schaeff, H., Kalscheuer, R., Goldberg, A.L., Brötz-Oesterhelt, H. 2016. Acyldepsipeptide antibiotics kill mycobacteria by preventing the physiological functions of the ClpP1P2 protease. Molecular Microbiology doi: 10.1111/mmi.13362.

Gersch, M., Famulla, K., Dahmen, M., Göbl, C., Malik, I., Richter, K., Korotkoc, V.S., Sass, P., Rübsamen-Schaeff, H., Madl, T., Brötz-Oesterhelt, H.*, Sieber, S.* 2015. AAA+ chaperones and acyldepsipeptides activate ClpP via conformational control. Nature Communications doi: 10.1038/ncomms7320.

Schiefer, A., Vollmer, J., Lämmer, C., Specht, S., Lentz, C., Ruebsamen-Schaeff, H., Brötz-Oesterhelt, H., Hoerauf, A., Pfarr, K. 2013. The ClpP peptidase of Wolbachia endobacteria is a novel target for drug development against filarial infections. Journal of Antimicrobial Chemotherapy 68, 1790-1800 doi:10.1093/iac/dkt105.

Sass, P., Josten, M., Famulla, K., Schiffer, G., Sahl, H.G., Hamoen, L., Brötz-Oesterhelt, H. 2011. Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proceedings of the National Academy of Science U.S.A, 108, 17474-17479 10.1073/pnas.1110385108 doi:10.1093/jac/dkt105

Lee, B.G., Park, E.Y., Jeon, H., Sung, K.H., Paulsen, H., Rübsamen-Schaeff, H., Brötz-Oesterhelt, H., Song, H.K. 2010. Structures of ClpP in complex with a novel class of antibiotics reveal its activation mechanism. Nature Structural and Molecular Biology, 17, 471-478 doi:10.1038/nsmb.1787

Brötz-Oesterhelt, H., Beyer, D., Kroll, H.P., Endermann, R., Ladel, C., Schroeder, W., Hinzen, B., Raddatz, S., Paulsen, H., Henninger, K., Bandow, J.E., Sahl, H.G., Labischinski, H. 2005. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nature Medicine, 11, 1082-1087 doi:10.1038/nm1306.