# Usnic Acid Derivatives as Inhibitors of Mycobacterium tuberculosis Uracil–DNA Glycosylase

## TL;DR

Scientists found that usnic acid derivatives can block a key DNA repair enzyme in TB bacteria, potentially improving current treatments.

## Contribution

Novel usnic acid derivatives were identified as inhibitors of Mycobacterium tuberculosis uracil–DNA glycosylase through virtual screening and experimental validation.

## Key findings

- Four usnic acid derivatives significantly inhibited MtbUng activity, with OL10-88-1 showing an IC50 of 26 ± 7 µM.
- Molecular docking suggests OL10-88-1 disrupts uracil recognition by occupying the active site and DNA-binding groove.
- The compounds also inhibited uracil–DNA glycosylases from E. coli, humans, and vaccinia virus.

## Abstract

Tuberculosis (TB) remains a global health issue exacerbated by spreading drug resistance and lengthy treatment regimens. Targeting bacterial DNA-repair pathways, particularly those counteracting host-generated genotoxic stress, represents a promising strategy to sensitize Mycobacterium tuberculosis to existing antibiotics. Through structure-based virtual screening of a compound library, we identified novel small-molecule inhibitors of M. tuberculosis uracil–DNA glycosylase (MtbUng), an enzyme essential for the repair of DNA damage inflicted by macrophage-produced reactive nitrogen species. Experimental validation revealed that four derivatives of usnic acid, a lichen-derived metabolite, significantly inhibited MtbUng activity, with the most potent compound, OL10-88-1, exhibiting IC50 26 ± 7 µM. Molecular docking suggests that OL10-88-1 inhibits MtbUng by occupying both the active site and the DNA-binding groove, thereby disrupting multiple steps of uracil recognition. The compounds also showed variable inhibitory activity against uracil–DNA glycosylases from Escherichia coli, humans, and vaccinia virus. Our findings establish that the compound could potentially be used in combination therapies to enhance the efficacy of current anti-TB drugs by exploiting the vulnerability of DNA-repair-deficient mycobacteria.