Site-specific modification of the anticancer and antituberculosis polyether salinomycin by biosynthetic engineering

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Salinomycin, a complex polyether ionophore, shows selective activity against cancer stem cells and latent tuberculosis.
• The mechanism underlying salinomycin's therapeutic effects remains largely unknown.

Purpose of the Study:

• To investigate the function of the salE gene in salinomycin biosynthesis.
• To characterize novel salinomycin analogues produced by salE deletion.
• To explore the potential of biosynthetic engineering for generating new drug candidates.

Main Methods:

• Gene deletion studies (salE knockout) in salinomycin-producing organisms.
• Structural elucidation of novel salinomycin analogues using spectroscopic techniques.
• Biochemical characterization of the SalE protein as a dehydratase.

Main Results:

• Deletion of the salE gene completely abolished salinomycin production.
• Two new salinomycin analogues were identified, featuring a C19 hydroxy group instead of the C18–C19 double bond.
• These analogues differed in the stereochemical configuration of their bis-spiroacetal moieties.
• The SalE protein was confirmed to function as a novel dehydratase in the salinomycin biosynthetic pathway.

Conclusions:

• The salE gene is essential for salinomycin production, encoding a novel dehydratase enzyme.
• Biosynthetic engineering by modifying the salE gene can redirect the oxidative cyclization pathway.
• This approach yields novel salinomycin analogues with potential applications in mechanism-of-action studies and drug development.