• CHASE M WEBB

      Articles written in Journal of Biosciences

    • Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA

      BRITTNEY M BUNN MIZHI XU CHASE M WEBB RAJESH VISWANATHAN

      More Details Abstract Fulltext PDF

      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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