# Exploration of the Fusidic Acid Structure Activity Space for Antibiotic Activity

## TL;DR

This study explores how modifying the structure of fusidic acid can improve its antibiotic activity, particularly against Gram-positive bacteria.

## Contribution

The study identifies specific structural modifications to fusidic acid that retain or enhance its antibacterial activity.

## Key findings

- Modifications to the A-ring alcohol of fusidic acid retained modest activity against Gram-positive bacteria.
- Side-chain carboxylic acid esters and C-ring oxidations were ineffective or poorly tolerated.
- The fusidic acid pyrazine-2-carboxylate may act as a pro-drug based on activity differences in assays.

## Abstract

Fusidic acid is a translation inhibitor with activity against major Gram-positive bacterial pathogens such as S. aureus. However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic acid scaffold to enhance activity against Gram-negative pathogens have not been explored. Using an activity-guided synthetic strategy, the tolerance of the tetracyclic natural product to derivatization at the A- and C-rings and its carboxylic acid side chain was explored with the goal of enhancing its activity spectrum and pharmacological properties. All side-chain carboxylic acid esters were inactive. Oxidation of the C-ring alcohol and oxime were not tolerated either. A number of esters of the A-ring alcohol retained modest activity against Gram-positive bacteria and were informative for future activity-guided studies. For the A-ring esters, differences in antibacterial activity relative to inhibitory activity in a ribosome in vitro translation assay suggested the possibility of a pro-druglike effect for the fusidic acid pyrazine-2-carboxylate. This study furthers the understanding of the activity of the fusidic acid scaffold against Gram-positive bacteria. These results suggest promise for future modification of the A-ring alcohol of fusidic acid in the advancement of its antibiotic properties.