Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA

The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenic infections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditional antibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exert...

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Bibliographic Details
Published inJournal of biosciences Vol. 46; no. 2
Main Authors Bunn, Brittney M, Xu, Mizhi, Webb, Chase M, Viswanathan, Rajesh
Format Journal Article
LanguageEnglish
Published New Delhi Springer India 01.06.2021
Springer Nature B.V
Subjects
Amino acids
Antibiotics
Biocatalysts
Biomedical and Life Sciences
Biomedicine
Cell Biology
Drug resistance
Enzymes
Haemolysis
Homology
Indoles
Iron
Ketoglutaric acid
Life Sciences
Methicillin
Microbiology
Oxygenase
Pathogens
Plant Sciences
Staphylococcus aureus
Staphylococcus infections
Substrates
Tryptophan
Tryptophan synthase
Zoology
Antivirulence
Enzymology
Isonitriles
Natural products
MRSA
Tryptophan-derived bioactives
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Summary:The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenic infections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditional antibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exerting pressure, that cause resistance. Herein, we employed a thermophilic Thermotoga maritima tryptophan synthase ( Tm TrpB1) enzyme followed by an isonitrile synthase and Fe(II)-α-ketoglutarate-dependent oxygenase, in sequence as biocatalysts to produce antivirulent indole vinyl isonitriles. We report on conversion of simple derivatives of indoles to their C3-vinyl isonitriles, as the enzymes employed here demonstrated broader substrate tolerance. In toto , eight distinct L-Tryptophan derived α-amino acids ( 7 ) were converted to their bioactive vinyl isonitriles ( 3 ) by action of an isonitrile synthase (WelI1) and an Fe(II)-α-ketoglutarate-dependent oxygenase (WelI3) yielding structural variants possessing antivirulence against MRSA. These indole vinyl isonitriles at 10 μg/mL are effective as antivirulent compounds against MRSA, as evidenced through analysis of rabbit blood hemolysis assay. Based on a homology modelling exercise, of enzyme-substrate complexes, we deduced potential three dimensional alignments of active sites and glean mechanistic insights into the substrate tolerance of the Fe(II)-α-ketoglutarate-dependent oxygenase. Graphic abstract
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ISSN:0250-5991
0973-7138
DOI:10.1007/s12038-021-00156-4