Oligomycin: Definition, Mechanism and Application

What is oligomycin?

Oligomycin, a macrolide antibiotic produced by Streptomyces, blocks oxidative phosphorylation by specifically inhibiting the F0 subunit of mitochondrial ATP synthase (F0F1-ATPase), thereby interfering with cellular energy metabolism. There are many isomers of oligomycin, such as oligomycin A, B and C, which differ in biological activity and inhibitory potency.

The structure and molecular configuration of oligomycin B were initially elucidated by combining spectroscopic and X-ray crystallographic data, and the structures of oligomycin A and C were subsequently inferred based on chemical associations between their degradation products and oligomycin B derivatives. Oligomycin A is the most potent isomer with the formula C45H74O11. It can effectively block the proton channel of ATP synthase, and then prevent the phosphorylation of ADP to ATP, inhibit cell respiration and oxidative phosphorylation. Oligomycin A also has antifungal, antitumor and antiparasitic activities. In contrast, oligomycin B (C45H72O12) and C (C45H74O10) can inhibit ATP synthase, but not as effectively as oligomycin A.

Oligomycin is not only used to study mitochondrial function and cell metabolism, but also undergoes preclinical evaluation as an anticancer drug candidate. However, due to its low solubility in water and other biocompatible solvents, further clinical development is restricted. Nevertheless, as a bioactive substance with wide application value, oligomycin still shows remarkable potential in the field of biomedical research.

Oligomycin at BOC Sciences

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Mechanism of oligomycin

Oligomycin is a class of cytotoxic macrolides with a 26-membered ring structure containing 17 stereocentes, nine of which are located in the propionic acid-derived region (C4-C14) and eight in the spiroacetal fragment (C20-C34). Oligomycin blocks oxidative phosphorylation by inhibiting ATP biosynthesis in mitochondria. Oligomycin first binds to oligomycin sensitivity endowing protein (OSCP), a regulatory protein located in the stem of the F0-F1 ATP synthase complex, to form a complex. The formation of oligomycin-OSCP complex interferes with the transport of protons across the inner mitochondrial membrane, thus inhibiting the production of ATP and affecting the growth and survival of cells.

In addition, the study also revealed that oligomycin can activate the nuclear factor E2-associated factor 2 (Nrf2) antioxidant signaling pathway, helping to reduce the damage caused by oxidative stress on cells, which may enhance its anti-tumor activity. These findings provide a theoretical basis for the development of more selective oligomycin derivatives as novel antitumor drugs.

Oligomycin in cancer therapy

K-Ras mutated cancer therapy: Oligomycin compounds were found to inhibit membrane localization of the oncogene K-Ras, suggesting that they could be potential chemotherapy agents for treating K-Ras mutated cancers. These compounds are cytotoxic to human colorectal cancer cells and are able to significantly inhibit the efflux pump function of P-glycoprotein (P-gp), with some of them being as potent as the positive control verapamil.

Small cell lung cancer (SCLC) treatment: Studies have shown that oligomycin A can effectively inhibit tumor stem cells in small cell lung cancer (SCLC), reducing their sphere-forming capacity and clonogenesis potential. This suggests that oligomycin A inhibits the growth and spread of tumors by inhibiting the metabolic activity of CSCs, limiting their ability to self-renew and proliferate.

Breast cancer therapy: In breast cancer cells, oligomycin A promotes apoptosis by inducing mitochondrial depolarization and activating apoptotic pathways such as Caspase-3. In addition, the compound further enhances the apoptosis effect by increasing the level of reactive oxygen species (ROS). In the breast cancer metastasis model, oligomycin A is particularly effective on HER2-positive and Luminal A/B subtype breast cancer cells, inhibiting the invasion and metastasis of cancer cells by inhibiting energy metabolism and survival ability.

Melanoma treatment: Oligomycin A can induce melanoma cells to undergo a transition from apoptosis to pyrodeath by inhibiting mitochondrial function and inducing intracellular oxidative stress. The delivery of oligomycin A by nanocarriers can significantly enhance the programmed cell death (PCD) process and is used in combination with immune checkpoint inhibitors to achieve better immunotherapy effects.

Liver cancer treatment: SALL4 is a protein that is essential for early embryonic development, but it is usually silent in adult tissue. However, the protein has been found to be reactivated in a variety of cancers, including about 30-50% of hepatocellular carcinomas (HCC). Bardeesy et al. found that the natural compound oligomycin is more effective than the existing HCC drug sorafenib and has little toxicity at effective doses. Oligomycin combined with sorafenib can further reduce the growth of SALL4-connected HCC tumors in vivo.

Research on oligomycin

Nanoagonist containing oligomycin activates pyroapoptosis

Programmed cell death (PCD) plays a very important role in fighting cancer cells and inducing cell death. However, due to the multidrug resistance of cancer, malignant tumor cells often become resistant to commonly used anti-cancer drugs that induce apoptosis. Ji et al. formed a biocompatible and mitochondria targeted self-assembling nanomaterial through the conjugating of oligomycin A and IR820, which can be disassembled and released under near-infrared laser irradiation, resulting in synthesis inhibition within the ATP electron transport chain and loss of mitochondrial function. This process may trigger electron leakage within mitochondria and induce active substances to suddenly release oxygen free radicals, thereby activating the downstream signaling pathway of pyroapoptosis, an emerging mitochondrial related PCD pathway. This assembled nano-agonist OA@IR820 can actively induce significant oxidative stress-mediated apoptosis in malignant tumor treatment in vitro and in vivo, and is a promising tumor treatment method.

The conjugation of oligomycin a and IR820 forms a self-assembled nanomaterial. (Ji, P., 2022)

Regulatory factors affect oligomycin synthesis in Streptomyces

Streptomyces is a class of Gram-positive bacteria with branched mycelia. As an important source of bioactive compounds, pharmaceutical chemicals and new drugs, its secondary metabolites have been widely studied and applied. According to statistics, more than two-thirds of the antibacterial and anti-tumor bioactive substances currently come from secondary metabolites of Streptomyces. The transcription regulatory factors that affect secondary metabolism of Streptomyces are divided into three types, including global regulatory factors, intra-cluster regulatory factors and multiple-effect regulatory factors. The researchers knocked out and overexpressed the transcriptional regulators SPA7074, SPA0520, and LuxR-2306 related to Streptomyces Aact12. The expression of the oligomycin synthesis gene cluster of Act12 was activated, and the production and antibacterial activity of oligomycin D were greatly improved.

Reference

1. Ji, P., et al. Modulation of mitochondrial electron transport chain by pyroptosis nanoagonists for photoresponsive tumor destruction. Nano Today. 2022, 44: 101511.