Actinonin ((-)-Actinonin) 是一种由放线菌产生的天然抗菌剂。Actinonin 抑制氨肽酶 M，氨肽酶 N 和亮氨酸氨肽酶。Actinonin 是一种有效的可逆肽去甲酰基酶 (PDF) 抑制剂，Ki 为 0.28 nM。Actinonin 还抑制 MMP-1，MMP-3，MMP-8，MMP-9 和 hmeprin α 的 Ki 值分别为 300 nM，1,700 nM，190 nM，330 nM 和 20 nM。Actinonin 是一种凋亡诱导剂，具有抗增殖和抗肿瘤活性。
Ki: 0.28 nM (Peptide deformylase (PDF)), 300 nM (MMP-1), 1,700 nM (MMP-3), 190 nM (MMP-8), 330 nM (MMP-9), and 20 nM (hmeprin α)
Apoptosis
Aminopeptidase M, Aminopeptidase N and Leucine aminopeptidase
Actinonin inhibits cell growth in various human tumor cell lines. The IC
50
of 4, 6.9, 12.8, 16.6, 27.4, 15.7 and 49.3 μM for Raji cells, MDA-MB-468 cells,PC3 cells, SK-LC-19 cells, Hela cells, HT-1080 cells and AL67 cells, respectively.
HsPDF is a critical target of actinonin and that the inhibition of this protein in the mitochondria leads to cell death in tumor cells. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner.
Actinonin is a potent inhibitor of all three forms (Zn-, Ni-, and Fe-) of peptide deformylases from both
S. aureus
and
E. coli
bacteria. Under the assay conditions, the IC
50
values for Actinonin are 90, 3, 0.8, and 11 nM for Zn-PDF (
E. coli
), Ni-PDF (
E. coli
), Fe-PDF (
E. coli
), and Ni-PDF (
S. aureus
), respectively.
Actinonin is active against Gram-positive bacteria, including
S. aureus
(MIC value of 8-16 µg/mL),
Streptococcus pyogenes
(MIC value of 8 µg/mL) and
Streptococcus epidermidis
(MIC value of 2-4 µg/mL). Actinonin is also active against fastidious Gramne-gative bacteria, such as
H. influenzae
(MIC value of 1-2 µg/mL),
Moraxella catarrhalis
(MIC value of 0.5 µg/mL), and
Neisseria gonorrheae
(MIC value of 1-4 µg/mL). Actinonin is very active against the
H. influenzae acr
(MIC value of 0.13 µg/mL) and
E. coli acr
(MIC value of 0.25 µg/mL) efflux pump mutants.
Actinonin has been safely administered to mice as an antibiotic at doses up to 400 mg/kg. Actinonin does not appear to have significant toxicity to normal tissues, despite its antitumor activity in vitro. Remarkably, Actinonin exhibits significant antitumor activity when given i.p. or orally in a CWR22 human prostate tumor xenograft model in nude mice. During treatment, the animals show no signs of toxicity.