Antibacterial activity of singly and doubly modified salinomycin derivatives |
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| Affiliation: | 1. Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland;2. Department of Pharmaceutical Microbiology, Centre for Preclinical Research and Technology (CePT), Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland;1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;2. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;3. University of Chinese Academy of Sciences, Beijing 100049, China;1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;2. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;1. Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89 b, 61-614 Poznań, Poland;2. Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland;1. Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland;2. Institute of Low Temperature and Structure Research, Polish Academy of Sciences, PO Box 1410, 50-950 Wrocław, Poland;1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States;2. Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61‒614 Poznań, Poland |
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| 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. |
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| Keywords: | Polyether ionophores Semi-synthetic analogs Gram-positive bacteria MRSA Bacterial biofilm Genotoxicity |
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