Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA

• Published in: Journal of biosciences Vol. 46; no. 2
• Main Authors: Bunn, Brittney M, Xu, Mizhi, Webb, Chase M, Viswanathan, Rajesh
• Format: Journal Article
• Language: English
• 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
• ISSN: 0250-5991; 0973-7138
• DOI: 10.1007/s12038-021-00156-4

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