Optimization of Actinomycin D Structure for Antifungal Activity: Strategies to Improve Combat Against Fungal Infections

Actinomycin D (ActD), initially discovered as an antibiotic with anticancer potential, was discontinued as a chemotherapeutic agent due to severe side effects, including bone marrow and liver toxicity. However, ActD demonstrates significant antimicrobial activity, with minimum inhibitory concentrations (MICs) of 0.15 μg/mL against Staphylococcus and Bacillus species, as well as mild antifungal effects. These properties are especially important in the context of rising invasive Candida infections, which affect over 200,000 patients annually and face growing concerns over drug resistance and limited treatment options. This study explores strategies to optimize the structure of ActD for enhanced antifungal activity against Candida species while minimizing its cytotoxicity. ActD’s peptide component and chromophore were synthesized separately and biological screening, including MIC determination and cytotoxicity tests, was performed. Additionally, organic fragments with antimicrobial properties—curcumin, carvacrol, ferulic acid, and cinnamic acid—were tested for their ability to improve ActD’s antifungal efficacy. We also analyzed the peptide length and amino acid composition of ActD to identify structural modifications that could enhance its activity. Our findings show that the peptide component alone is biologically inactive, while the chromophore exhibits antifungal activity against Candida parapsilosis at 250 μg/mL. Notably, all fragments tested showed reduced cytotoxic effects on MRC-5 fibroblasts. These preliminary results highlight the potential of the ActD chromophore as an optimized antifungal agent, offering a promising strategy for combating Candida infections and mixed Candida-Staphylococcus infections, addressing a critical unmet medical need.