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C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis

Bag, K and Pal, AK and Basu, S and Singla, M and Sarkar, B and Chatterji, D and Maiti, PK and Ghosh, A and Jayaraman, N (2023) C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis. In: ACS Omega, 8 (23). pp. 20513-20523.

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Official URL: https://doi.org/10.1021/acsomega.3c00822


Hyperphosphorylated nucleotide (p)ppGpp, synthesized by Rel protein, regulates the stringent response pathway responsible for biofilm and persister cell growth in mycobacteria. The discovery of vitamin C as an inhibitor of Rel protein activities raises the prospect of tetrone lactones to prevent such pathways. The closely related isotetrone lactone derivatives are identified herein as inhibitors of the above processes in a mycobacterium. Synthesis and biochemical evaluations show that an isotetrone possessing phenyl substituent at C-4 inhibit the biofilm formation at 400 μg mL-1, 84 h post-exposure, followed by moderate inhibition by the isotetrone possessing the p-hydroxyphenyl substituent. The latter isotetrone inhibits the growth of persister cells at 400 μg mL-1 f.c. when monitored for 2 weeks, under PBS starvation. Isotetrones also potentiate the inhibition of antibiotic-tolerant regrowth of cells by ciprofloxacin (0.75 μg mL-1) and thus act as bioenhancers. Molecular dynamics studies show that isotetrone derivatives bind to the RelMsm protein more efficiently than vitamin C at a binding site possessing serine, threonine, lysine, and arginine.

Item Type: Journal Article
Publication: ACS Omega
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to the American Chemical Society.
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Chemical Sciences > Organic Chemistry
Division of Physical & Mathematical Sciences > Physics
Date Deposited: 25 Jul 2023 04:59
Last Modified: 25 Jul 2023 04:59
URI: https://eprints.iisc.ac.in/id/eprint/82586

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