# Design, Synthesis, and Anti-Biofilm Activity of C-28 Modified Betulinic Acid Derivatives Targeting SarA in Drug-Resistant Staphylococcus aureus

## TL;DR

Scientists designed new betulinic acid derivatives that inhibit biofilm formation in drug-resistant Staphylococcus aureus.

## Contribution

The study introduces C-28 modified betulinic acid derivatives that target SarA to combat drug-resistant Staphylococcus aureus.

## Key findings

- Compound 3d showed strong antibacterial activity against Staphylococcus aureus and VRSA.
- Molecular docking and dynamics studies suggest 3d binds to SarA, a key biofilm regulator.
- 3d significantly suppressed biofilm formation and exhibited bactericidal effects.

## Abstract

To address the urgent challenge of antimicrobial resistance, a series of twenty novel C-28 modified betulinic acid derivatives was designed and synthesized. Several derivatives, particularly 3b, 3d, 3e, and 3o, displayed notable antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus (VRSA). The most active compound, 3d, was subjected to further mechanistic evaluation: it produced concentration-dependent inhibition zones in Oxford cup assays, exhibited bactericidal kinetics in time-kill studies, and significantly suppressed biofilm formation. Molecular docking suggested that the anti-biofilm activity of 3d may be mediated through binding to the staphylococcal accessory regulator A (SarA), a key transcriptional regulator of biofilm formation. The molecular dynamics study provided additional confirmation of the effective binding between 3d and SarA. These results highlight compound 3d as a promising lead for the development of novel anti-biofilm agents targeting drug-resistant Gram-positive infections.