3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Molecular Biology

Background:

• Fusidic acid (FA) is a clinically used antibiotic effective against *Staphylococcus aureus*.
• The limited antimicrobial spectrum of FA restricts its therapeutic applications.
• Development of novel FA derivatives is crucial for expanding antimicrobial treatment options.

Purpose of the Study:

• To synthesize and evaluate novel fusidic acid (FA) analogues with modified amino groups.
• To identify the biological targets and mechanisms of action for these new FA derivatives.
• To assess the antimicrobial and fungicidal potential of synthesized compounds.

Main Methods:

• Synthesis of 20 FA analogues incorporating aliphatic, aromatic amino, spermine, and spermidine moieties.
• Antimicrobial susceptibility testing against *Staphylococcus aureus* (MRSA), *Escherichia coli*, *Acinetobacter baumannii*, and *Pseudomonas aeruginosa*.
• Fungicidal assays against *Candida albicans* and *Cryptococcus neoformans*.
• Membrane activity studies (lipid disordering, pore formation).
• Molecular docking simulations to predict interactions with protein targets, specifically elongation factor EF-G.

Main Results:

• Pyrazinecarboxamide-substituted analogues demonstrated potent activity against MRSA (MIC ≤ 0.25 μg/mL).
• Spermine and spermidine derivatives exhibited broad-spectrum activity against Gram-negative bacteria and significant fungicidal effects.
• Compounds containing spermine and spermidine disordered bacterial membranes via a detergent effect.
• Spermine derivatives formed ion-permeable pores in lipid bilayers.
• Molecular docking suggested inhibition of elongation factor EF-G, with polyamine substituents enhancing complex stability.

Conclusions:

• Novel FA derivatives possess broad-spectrum antimicrobial and fungicidal properties.
• The observed activity is attributed to both membrane disruption and inhibition of protein synthesis elongation factor EF-G.
• These findings suggest promising potential for developing new FA-based antibiotics targeting resistant pathogens.