Salinomycin is an antibacterial and coccidiostat ionophore 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 bact ...

, 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 its c ...

''. Salinomycin is inactive against fungi such as ''Candida'' and Gram-negative bacteria.

Cancer research

Pre-clinical

Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer

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 o ...

s in mice at least 100 times more effectively than the anti-cancer drug paclitaxel. The study screened 16,000 different chemical compounds and found that only a small subset, including salinomycin and etoposide, targeted cancer stem cells responsible for metastasis and relapse. The mechanism of action 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 incl ...

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 coccidiostat.

Biosynthesis

A team from the University of Cambridge 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 salbostatin was isolated. ''S. albus'' is known to produce white aerial mycelium. References Further reading * External linksType strain of ''St ...

'' DSM 41398. This has shown that the polyketide backbone of salinomycin is synthesised on an assembly line of nine polyketide synthase) 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