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    • Keywords

       

      Antivirulence; Enzymology; Isonitriles; MRSA; Natural products; Tryptophan-derived bioactives

    • Abstract

       

      The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenicinfections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditionalantibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exerting pressure, that causeresistance. Herein, we employed a thermophilic Thermotoga maritima tryptophan synthase (TmTrpB1) enzymefollowed by an isonitrile synthase and Fe(II)-alpha-ketoglutarate-dependent oxygenase, in sequence as biocatalyststo produce antivirulent indole vinyl isonitriles. We report on conversion of simple derivatives of indoles to theirC3-vinyl isonitriles, as the enzymes employed here demonstrated broader substrate tolerance. In toto, eightdistinct L-Tryptophan derived alpha-amino acids (7) were converted to their bioactive vinyl isonitriles (3) by actionof an isonitrile synthase (WelI1) and an Fe(II)-a-ketoglutarate-dependent oxygenase (WelI3) yielding structuralvariants possessing antivirulence against MRSA. These indole vinyl isonitriles at 10 micro-g/mL are effective asantivirulent compounds against MRSA, as evidenced through analysis of rabbit blood hemolysis assay. Basedon a homology modelling exercise, of enzyme-substrate complexes, we deduced potential three dimensionalalignments of active sites and glean mechanistic insights into the substrate tolerance of the Fe(II)-alpha-ketoglutarate-dependent oxygenase.

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    • Author Affiliations

       

      BRITTNEY M BUNN1 MIZHI XU2 CHASE M WEBB3 RAJESH VISWANATHAN4

      1. Thermo Fisher Scientific, Cleveland, OH, USA
      2. Department of Chemistry, Georgia Institute of Technology, Atlanta, GA, USA
      3. Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA, USA
      4. Department of Chemistry and Biology, Indian Institute of Science Education and Research Tirupati, Tirupati, India
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