Marine-Derived

Actinomycins are a group of chromopeptide lactone antibiotics. To date, 42 actinomycins have isolated and identified from many species of Streptomyces, including actinomycin D, N-demethylactinomycins; actinomycin C, actinomycin F, actinomycin Z, actinomycin G, and actinomycin Y. Some actinomycin analogs, such as methylated actinomycin D, an actinomycin Z analog having an additional oxygen bridge between the chromophore and β-depsipentapeptide; actinomycins D1–D4 and neo-actinomycins A and B; possess structurally modified cyclopeptide rings or chromophore.
Initiatives to develop actinomycin analogs with superior bioactivities have heavily rooted in precursor-directed biosynthesis. Actinomycins, commonly employed clinically in anticancer therapeutic regimes; exhibit excellent antitumor activity. The core phenoxazinone chromophore intercalates between the stacked nucleobases at guanine/cytosine sites of DNA whereas the pentapeptide elements bind to the minor groove; these binding interactions effectively inhibit duplication and transcription processes in tumor cells. Exemplary in this fashion, actinomycin D is a highly effective chemotherapeutic used to treat Wilm’s kidney tumors; trophoblastic tumors, and rhabdomyosarcoma.

The expression of a stem-cell

Actinomycin D also specifically targets and down-regulates the expression of a stem-cell transcription factor; Sox-2; this protein facilitates depletion of the stem-cell population resulting in the inability of breast cancer cells to initiate tumor progression. Low doses of actinomycin D specifically activate p53-dependent transcription; enhancing the activity of chemotherapeutic drug-induced killing of p53 positive human tumor cells.

Actinomycins are also able to inhibit some viruses such as the coxsackievirus B3 and HIV-1; the causative agent of AIDS. The combination of these novel activities and potential in human health makes actinomycin D one of the most promising candidates for medicinal development campaigns. Moreover, actinomycins often display strong antimicrobial activities. Potent antibacterial activities against human pathogens; human pathogenic fungi, as well as aquatic pathogenic bacteria are well known.

Marine-derived producer

Therefore the actinomycin D is a vital antibiotic in the treatment of Wilms’ tumor, trophoblastic tumors; rhabdomyosarcomas. Here, we have identified and characterized a new actinomycin D BGC (acn); but in marine-derived producer S. costaricanus SCSIO ZS0073 by carrying out whole-genome sequencing and systematic gene disruptions. Relative to the gene cluster for actinomycin of S. chrysomallus and S. antibiotics IMRU3720, the size of the acn cluster in S. costaricanus SCSIO ZS0073 is smaller.
In silico analysis, gene inactivation and metabolomics data enabled us to deduce the biosynthetic pathway leading to actinomycin D in S. costaricanusSCSIO ZS0073. They furthermore determined the acn cluster boundaries and elucidated the functions of positive regulatory genes acnWU4RO; along with the cytochrome P450 gene acne which is responsible for installing the 4-oxoproline seen in actinomycin Xoβ.
The discovery of this new actinomycin BGC advances initiatives to engineer new actinomycin D analogs for clinical use and to explore the still elusive mechanism of actinomycin 4-MHA-pentapeptide monomer dimerization en route to intact actinomycins.