Activity of singly and doubly modified derivatives of C20-epi-salinomycin against Staphylococcus strains

• Published in: Journal of antibiotics Vol. 75; no. 8; pp. 445 - 453
• Main Authors: Czerwonka, Dominika, Podsiad, Małgorzata, Stefańska, Joanna, Antoszczak, Michał, Huczyński, Adam
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2022; Nature Publishing Group
• Subjects: 639/638/309/2144; 639/638/403/935; 639/638/549/977; Acylation; Analogs; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Bacteria; Bacteriology; Biofilms; Biological activity; Biomedical and Life Sciences; Bioorganic Chemistry; Chemical modification; Drug development; Esters; Genotoxicity; Gram-positive bacteria; Life Sciences; Medicinal Chemistry; Microbiology; Organic Chemistry; Protozoa; Salinomycin; Stereochemistry; Strains (organisms); Synthesis; Veterinary medicine
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-022-00536-4

Natural polyether ionophore salinomycin ( Sal ) has been widely used in veterinary medicine as an antibiotic effective in the treatment of coccidian protozoa and Gram-positive bacteria. Moreover, chemical modification of the Sal structure has been found to be a promising strategy to generate semisynthetic analogs with biological activity profiles improved relative to those of the native compound. In this context, we synthesized and thoroughly evaluated the antibacterial potential of a library of C1/C20 singly and doubly modified derivatives of C20-epi-salinomycin, that is, analogs of Sal with inversed stereochemistry at the C20 position. Among the synthesized analog structures, the most promising antibacterial active agents were those obtained via regioselective O -acylation of C20-epi-hydroxyl, particularly esters 7 , 9 , and 11 . Such C20 singly modified compounds showed excellent inhibitory activity against planktonic staphylococci, both standard and clinical strains, and revealed potential in preventing the formation of bacterial biofilms. In combination with their non-genotoxic properties, these Sal derivatives represent attractive candidates for further antimicrobial drug development.