Development of a New Inhibitor of Bacterial Cystathionine γ-Lyase Based on 6-Bromoindole and Aminothiophene

• Published in: Molecular biology (New York) 2024, Vol.58 (6), p.1082-1088
• Main Authors: Novikov, R. A., Platonov, D. N., Belyy, A. Yu, Potapov, K. V., Novikov, M. A., Tomilov, Yu. V., Kechko, O. I., Seregina, T. A., Solyev, P. N., Mitkevich, V. A.
• Format: Article
• Language: English
• Subjects: Alkylation; Antibacterial activity; Biochemistry; Biomedical and Life Sciences; Cystathionine g-lyase; Gentamicin; Human Genetics; Hydrogen sulfide; Life Sciences; Production and Structural–Functional Analysis of Antimicrobials
• ISSN: 0026-8933; 1608-3245
• DOI: 10.1134/S0026893324700584

Cystathionine-γ-lyase (CSE) is a key enzyme for H 2 S generation in the pathogenic bacteria Sta-phylococcus aureus , Pseudomonas aeruginosa , etc. Suppression of CSE activity significantly increases the antibiotic susceptibility of bacteria. In this work a method to synthesize a novel indole-based CSE inhibitor, 3-amino-5-[(6-bromo-1 H -indol-1-yl)methyl]thiophene, named MNS1, has been developed. The synthesis of MNS1 is based on the modification of substituted thiophene as a main structural fragment, which is involved in alkylation of 6-bromoindole at final steps. The dissociation constant of the MNS1 complex with S. aureus CSE ( Sa CSE) is 0.5 μM, one order of magnitude lower than with human CSE (hCSE). MNS1 was shown to efficiently enhance the antibacterial effect of gentamicin against Bacillus subtilis , suggesting its possible use as an antibiotic potentiator to inhibit the growth of CSE-expressing bacterial cells.