Salinomycin is an

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

and

coccidiostat A coccidiostat is an antiprotozoal agent that acts upon Coccidia parasites. Examples include: * Amprolium * Arprinocid * Artemether * Clazuril * Clopidol * Decoquinate * Diclazuril * Dinitolmide * Ethopabate * Halofuginone * Lasalocid * M ...

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...

therapeutic drug.

Antibacterial activity

Salinomycin and its derivatives exhibit high antimicrobial activity against

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bac ...

, including the most problematic bacteria strains such as methicillin-resistant ''Staphylococcus aureus'' and methicillin-resistant ''Staphylococcus epidermidis'', and ''

Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on it ...

''. Salinomycin is inactive against fungi such as ''Candida'' and

Gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

Cancer research

Pre-clinical

Salinomycin has been shown by Piyush Gupta et al. of the

Massachusetts Institute of Technology The Massachusetts Institute of Technology (MIT) is a private land-grant research university in Cambridge, Massachusetts. Established in 1861, MIT has played a key role in the development of modern technology and science, and is one of th ...

and the

Broad Institute The Eli and Edythe L. Broad Institute of MIT and Harvard (IPA: , pronunciation respelling: ), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The insti ...

to kill

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...

s in mice at least 100 times more effectively than the anti-cancer drug

paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical ca ...

. The study screened 16,000 different chemical compounds and found that only a small subset, including salinomycin and

etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...

, targeted

cancer stem cells Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sampl ...

responsible for metastasis and relapse. The

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...

by which salinomycin kills cancer stem cells involves lysosomal iron sequestration, leading to the production of reactive oxygen species, lysosome membrane permeabilization and ferroptosis . Studies performed in 2011 showed that salinomycin could induce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

of human cancer cells at higher concentrations. C20 amino derivatives such as ironomycin have shown to be more potent in vitro models of persister cancer cells and in vivo . Promising results from a few clinical pilot studies reveal that salinomycin is able to effectively eliminate cancer stem cells and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both cancer stem cells and therapy-resistant cancer cells (persister) may define the compound as a novel and an effective anticancer drug. It has been also shown that salinomycin and its derivatives exhibit potent antiproliferative activity against the drug-resistant cancer cell lines. Salinomycin is the key compound in the pharmaceutical company Verastem's efforts to produce an anti-cancer-stem-cell drug.

Use in agriculture

Salinomycin is used in chicken feed as a

Biosynthesis

A team from the

University of Cambridge , mottoeng = Literal: From here, light and sacred draughts. Non literal: From this place, we gain enlightenment and precious knowledge. , established = , other_name = The Chancellor, Masters and Schola ...

has cloned and sequenced the biosynthetic cluster responsible for salinomycin production, from ''

Streptomyces albus ''Streptomyces albus'' is a bacterial species from which the pseudodisaccharide aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis a ...

'' DSM 41398. This has shown that the

polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

backbone of salinomycin is synthesised on an assembly line of nine

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

) multienzymes. Furthermore, the cluster contains genes involved in oxidative cyclization including ''salC'' (epoxidase) and ''salBI/BII/BIII'' (epoxide hydrolase) genes. The cluster also contains genes suspected to be involved in self-resistance, export, precursor supply and regulation. The cluster contains a NRPS-like carrier protein, SalX, that is suspected to tether “pre-salinomycin” during oxidative cyclization. By inactivating salC the researchers have demonstrated that salinomycin biosynthesis proceeds via a diene intermediate.

References