1. Antibacterial activity of singly and doubly modified salinomycin derivatives
- Author
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Adam Huczyński, Karolina Stępień, Michał Sulik, Michał Antoszczak, and Joanna Stefańska
- Subjects
medicine.drug_class ,Gram-positive bacteria ,Clinical Biochemistry ,Antibiotics ,Pharmaceutical Science ,Context (language use) ,Microbial Sensitivity Tests ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Molecular Biology ,Salinomycin ,Pyrans ,biology ,Bacteria ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Mutagenicity Tests ,Organic Chemistry ,Biofilm ,biology.organism_classification ,Combinatorial chemistry ,0104 chemical sciences ,Anti-Bacterial Agents ,Ciprofloxacin ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Antibacterial activity ,Genotoxicity ,medicine.drug - Abstract
The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2–3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1–4 µg mL−1. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic – ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives.
- Published
- 2020