The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease.
A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degradation. Here, we analyse the molecular mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hsp100 adenosine triphosphatases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.
Kirstein
Janine
J
Institut für Biologie-Mikrobiologie, FU Berlin, Berlin, Germany.
Hoffmann
Anja
A
Lilie
Hauke
H
Schmidt
Ronny
R
Rübsamen-Waigmann
Helga
H
Brötz-Oesterhelt
Heike
H
Mogk
Axel
A
Turgay
Kürşad
K
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002364:Caseins / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D049071:Endopeptidase Clp / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006360:Heat-Shock Proteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary
D000900:Anti-Bacterial Agents; D002364:Caseins; D047630:Depsipeptides; D006360:Heat-Shock Proteins; D049071:Endopeptidase Clp