Antitumor Antibiotics: Definition and Classification

Cancer is a serious threat to human health, and the burden of cancer continues to grow worldwide. Therefore, the discovery of new anticancer drugs and the search for effective cancer treatment have been the focus of cutting-edge research. In terms of drug research and development, metabolic products produced in microbial life activities are an important source of many anti-tumor drugs, and a variety of anti-tumor drugs derived from microorganisms have been widely used in clinical practice. Antitumor antibiotics are chemical substances produced by microorganisms with antitumor activity. According to their structure, they can be divided into peptides, enedienes, macrolides, anthracyclines, benzopyrrole and so on.

Antitumor antibiotics at BOC Sciences

Peptide antibiotics

Classic antitumor reagents, such as actinomycin D, bleomycin, romidepine, etc., all have peptide structural characteristics. In addition to peptide bonds and 20 alpha-amino acids, peptide antitumor reagents may also contain glycosidic bonds, ester bonds, lactone rings or fatty acids, or other non-protein-derived amino acids. Peptide antitumor drugs have the advantages of small molecular weight, simple structure, easy modification, and few adverse reactions.

In 1940, Waksman isolated actinomycin D from Streptomyces parvullus. In the early stages of the research, researchers found that actinomycin D has strong antibacterial activity. Later, its strong anti-tumor biological activity was revealed. Its mechanism of action is to interfere with cell transcription by inhibiting RNA synthesis and acting on mRNA. The biosynthesis of actinomycin is mainly divided into three stages: first, 4-methyl-3-hydroxyanthranilic acid (4-MHA) is synthesized through the kynurenine pathway; then 3-hydroxy-4-methyl-anthranilate pentapeptide lactone is formed under the assembly of a non-ribosomal enzyme system; finally, the two produced 3-hydroxy-4-methyl-anthranilate pentapeptide lactone are condensed under the catalysis of phenoxazinone compound (PHS) to form a phenoxazinone chromophore.

Bleomycin is a glycopeptide antibiotic extracted in 1966 from Streptomyces verticillus culture medium. It is a non-specific drug for the cell cycle. Its anti-tumor function mainly affects the structure and function of DNA, causing DNA single-strand breaks and preventing DNA replication. Bleomycin has a hybrid peptide-polyketide structure and disaccharide unit, in which the peptide-polyketide skeleton consists of 9 amino acids, one acetic acid and two s-adenosylmethionine. NRPSs, polyketide synthetases (PKSs) and glycosyl synthetases are involved in the synthesis of bleomycin.

Romidesin, a reclipidic compound isolated from Crobacterium violaceum in 1994, is a broad-spectrum histone deacetylase (HDAC) inhibitor. There are three NRPS genes depA, depD and depE in the romidesine biosynthetic gene cluster, and two PKS genes depB and depC. The encoded proteins catalyze seven compound units to form the FK228 skeleton structure.

Indoquinones-mitomycin C

Mitomycin C is an antitumor antibiotic extracted from Streptomyces caespitosus. Its mechanism of action mainly activates alkylation and cross-linking of DNA through G-G interchain bonds in vivo, selectively inhibits DNA synthesis, and then inhibits cell mitosis, resulting in abnormal increase in the number of chromosomes. The mitomycin backbone is produced by AHBA and d-glucosamine under the action of the glycosyltransferase MitB.

Anthracycline antibiotics

Anthracyclines have a good inhibitory effect on solid tumors. They can induce an immune response to tumor cells while killing cancer cells.

Doxorubicin, an anti-tumor drug derived from Streptomyces peucetius var. caesius, works by damaging a cell's DNA. Its biosynthesis in Streptomyces mainly involves 24 key genes, and the main process has three steps: the production of ε-rhodomycin, the production of dTDP-L-daunosamine, the glycosylation of ε-rhodomycin and dTDP-L-daunosamine to produce rhodomycin D; then the production of doxorubicin through methylation, decarboxylation, and hydroxylation.

Doxorubicin is considered to be one of the most effective reagents for tumor chemotherapy. It inhibits tumor cell proliferation by inhibiting DNA and RNA synthesis, leading to tumor cell death. Due to its broad-spectrum antitumor activity, it is widely used in the treatment of acute and chronic leukemia, breast cancer, malignant lymphoma and lung cancer and other malignant tumors. Clinically, radiotherapy and surgery are the main treatment for cervical cancer, while radiotherapy and concurrent chemotherapy are the main treatment for patients with advanced cervical cancer. When combined chemotherapy with doxorubicin and cisplatin are given to patients with cervical cancer radiotherapy, the patient's disease control rate is significantly improved, and toxic and side effects are reduced.

Guanghuangmycin is a polyketide antitumor antibiotic with chloromylic acid structure isolated and purified from Streptomyces. It can be linked to the GC region of a gene, form a stable complex with DNA, and competitively inhibit the binding of SP1 to its target gene regulatory elements. The main biosynthetic pathway of Guanghumycin is: first, the synthesis of 4-demethylpremithrinone, which starts with the condensation reaction of acetyl-CoA mediated by type II polyketide synthase (PKS); then the synthesis of premithramycin B; finally, premithramycin B lactone is formed by mtmOIV oxygenase, which is spontaneously decarboxylated, and then reduced by mtmW ketoreductase to form Guanghumycin.

Macrolide antibiotics

Macrolide antibiotics are a class of antibiotics commonly used in clinic and have been used in clinic for more than 40 years. With the deepening of research, the anti-tumor activity of macrolide antibiotics has been paid more and more attention.

Ebomycin is a class of antitumor drugs isolated from Sorangium cellulosum So ce90. It has a similar mechanism of action to paclitaxel and is a microtubule stabilizer. Ebomycin biosynthesis is divided into four steps: initial thiazole ring synthesis, polyketone chain extension, cyclization release of polyketone chain, and post-product modification.

Rapamycin is a nitrotriene-containing macrolide antibiotic isolated from Streptomyces hygroscopic AYB-944, which has antifungal, antiproliferative and antitumor effects. The mechanism of rapamycin inhibiting tumor is to control the phosphorylation of various proteins related to translation and transcription, and affect the expression of tumor-forming factors. Rapamycin is synthesized through the polyketopeptide synthesis pathway, which is mainly divided into four steps: initiation of synthesis, extension of the polyketo chain, cyclization of the polyketo chain, and post-modification.

Enediyne antibiotics

Enediyne antibiotics are a new type of anti-tumor antibiotics. Enediyne structure is its active center, and it has good inhibitory activity against many kinds of tumors, especially blood tumors.

Lidarmycin is an antibiotic isolated from Streptomyces globisporus C-1027, which combines an active aromatic chromophore (AE) with an acidic carrier protein (LDP). AE is the active part of Lidamycin that plays anti-tumor role, and LDP's function is to protect against AE. The enediyne core of lidamycin is biosynthesized via acetyl-CoA and 7 malonyl-CoA units via the polyketo pathway of PKS SgcE.

Calicimycin is a class of enediyne antitumor antibiotics isolated from Micromonas aculeatus in 1986. The enediyne core structure, as a highly efficient DNA splitting agent, causes DNA breakage and death of tumor cells by binding to the DNA double helix groove. The synthesis of calicimycin is divided into four steps: formation of the α-ketopyrrole derivative, synthesis of the polykeone chain, formation of the precursor 3-hydroxyanthranilic acid, and finally formation of the benzooxazole ring, and further formation of calicimycin.

Benzoquinone ansa antibiotic-geldanamycin

Geldamycin, isolated from Streptomyces hygroscopicus var. geldanus var. nova in 1970, is a benzoquinone ansa antibiotic and was the first identified N-terminal inhibitor of heat shock protein 90 (Hsp90). Geldamycin can compete with ATP and bind specifically to the ATP binding site of Hsp90, thus affecting the function of Hsp90. The biosynthesis gene cluster of Geldamycin contains 16 genes, including PKS gene, precursor synthesis gene, post-modified enzyme gene, regulatory gene and so on.

Research on antitumor antibiotic

Eravacycline improves anti-PD1 immunotherapy

There is growing evidence that antibiotics reduce the effectiveness of anti-PD1 immunotherapy in cancer treatment. However, Peng et al. found through drug library screening that an antibiotic ervacycline (ERV) can improve the therapeutic effect of anti-PD1 immunotherapy in melanoma. ERV is a new fully synthetic tetracycline antibiotic. Administration of ERV significantly inhibits the growth of melanoma cells and promotes the polarization of M1 macrophages. At the same time, ERV induces autophagy by damaging mitochondria, enhances ROS production, and then activates p38 or JNK1/2, increases the binding of AP1 to the CCL5 promoter, thereby enhancing CCL5 secretion. Knockout of the Ccl5 gene attenuates ERV-triggered M1 macrophage polarization in melanoma cells. Clinical analysis shows that high expression of CCL5 is positively correlated with improved prognosis and enhanced anti-PD1 treatment in melanoma patients.

Liposomal antibiotic generates neoantigens

More and more evidence shows that the tumor flora is one of the important factors affecting the tumor progression, and the diagnosis and immunotherapy of the tumor flora are also the focus of current research. Killing microorganisms in tumors has the potential to expose more epitopes shared by microbes and cancer cells, better activating the immune response. To interpret the interrelationship between anti-tumor immunity, gut microbiome, and antibiotic therapy, Huang et al., University of North Carolina, delivered liposomes of the silver-carrying tinidazole complex (LipoAgTNZ) to in situ colorectal cancer tumors in bacteria-infected mice using a remote loading technique. Demonstrated the release of anti-tumor CD8 T cells by liposome delivery of antibiotics targeting anaerobic bacteria to remove bacteria from colorectal cancer tumors. Heterologous and homologous epitopes were analyzed based on genome-wide comparisons between host and colonizing bacteria. In the cancer-causing model of C. nucleocardium infection, T cells respond to epitopes shared by both C. nucleocardium and the host. Killing tumor-associated bacteria turns immune cold tumors into hot tumors and primes the immune system to recognize infected and uninfected tumor cells.

Illustration of remote loading by a silver nitrate gradient and drug release in response to low pH. (Wang, M., 2024)

References

1. Liu, N., et al. Eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5 mediated M1 macrophage polarization in melanoma. Biomaterials. 2025, 314: 122815.
2. Wang, M., et al. Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses. Nature Biotechnology. 2024, 42(8): 1263-1274.