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

Kingshuk Bag, Aditya Kumar Pal, Subhadip Basu, Mamta Singla, Biplab Sarkar, Dipankar Chatterji, Prabal Kumar Maiti, Anirban Ghosh, Narayanaswamy Jayaraman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)20513-20523
Number of pages11
JournalACS Omega
Volume8
Issue number23
DOIs
StatePublished - 13 Jun 2023
Externally publishedYes

ASJC Scopus subject areas

  • General Chemical Engineering
  • General Chemistry

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