Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.59 (
MIP
)
4,906
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Systematic genetic interaction profiles can reveal the mechanisms-of-action of bioactive compounds. The imipridone ONC201, which is currently in cancer clinical trials, has been ascribed a variety of different targets. To investigate the genetic dependencies of imipridone action, we screened a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout library in the presence of either ONC201 or its more potent analog ONC212. Loss of the mitochondrial matrix protease
CLPP
or the
mitochondrial intermediate peptidase
MIPEP conferred strong resistance to both compounds. Biochemical and surrogate genetic assays showed that impridones directly activate
CLPP
and that MIPEP is necessary for proteolytic maturation of
CLPP
into a catalytically competent form. Quantitative proteomic analysis of cells treated with ONC212 revealed degradation of many mitochondrial as well as nonmitochondrial proteins. Prompted by the conservation of ClpP from bacteria to humans, we found that the imipridones also activate ClpP from
Escherichia coli
,
Bacillus subtilis
, and
Staphylococcus aureus
in biochemical and genetic assays. ONC212 and acyldepsipeptide-4 (ADEP4), a known activator of bacterial ClpP, caused similar proteome-wide degradation profiles in
S. aureus
ONC212 suppressed the proliferation of a number of Gram-positive (
S. aureus
,
B. subtilis
, and
Enterococcus faecium
) and Gram-negative species (
E. coli
and
Neisseria gonorrhoeae
). Moreover, ONC212 enhanced the ability of rifampin to eradicate antibiotic-tolerant
S. aureus
persister cells. These results reveal the genetic dependencies of imipridone action in human cells and identify the imipridone scaffold as a new entry point for antibiotic development.
...
PMID:Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic Development. 3209 49
