Second-generation aryl isonitrile compounds targeting multidrug-resistant Staphylococcus aureus |
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Authors: | Kwaku Kyei-Baffour Haroon Mohammad Mohamed N. Seleem Mingji Dai |
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Affiliation: | 1. Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, United States;2. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, IN 47907, United States;3. Purdue Institute of Inflammation, Immunology and Infectious Disease, 610 Purdue Mall, West Lafayette, IN 47907, United States |
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Abstract: | Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 to 4?µM) and were safe to human keratinocytes. Compound 19, with an additional isonitrile group exhibited improved activity against MRSA compared to the first-generation lead compound. This compound emerged as a candidate worthy of further investigation and further reinforced the importance of the isonitrile functionality in the compounds’ anti-MRSA activity. In a murine skin wound model, 19 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. In summary, 19 was identified as a new lead aryl isonitrile compound effective against MRSA. |
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Keywords: | Corresponding authors at: Department of Comparative Pathobiology Purdue University College of Veterinary Medicine 625 Harrison St. West Lafayette IN 47907 United States (M.N. Seleem). Department of Chemistry and Center for Cancer Research 720 Clinic Drive West Lafayette IN 47907 United States (M. Dai). |
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