Precursor directed biosynthesis of aureobasidins

Area of Science:

• Biochemistry
• Mycology
• Medicinal Chemistry

Background:

• Aureobasidin A (AbA) is a cyclic depsipeptide with known antifungal properties.
• Understanding the structure-activity relationship of AbA is crucial for developing novel antifungal agents.

Purpose of the Study:

• To synthesize novel aureobasidin A (AbA) analogs by modifying specific amino acid residues.
• To investigate the incorporation of exogenous amino acids into the AbA structure.
• To compare the antifungal activities of the newly synthesized AbA analogs with the parent compound.

Main Methods:

• Production of AbA analogs using Aureobasidium pullulans R 106 c-712 in a defined medium.
• Chemical modification of amino acid positions 3, 4, 5, 6, and 8 within the AbA structure.
• Incorporation studies using L-[1-13C]-Valine to trace metabolic pathways.
• Comparative assessment of antifungal activities.

Main Results:

• Eight new AbA analogs were successfully produced by replacing constituent amino acids (at positions 3, 4, 5, 6, and 8) with analogous structures.
• Exogenous L-[1-13C]-Valine was incorporated into specific valine-related moieties (positions 2, 7, and 9) but did not replace them.
• The study reports, for the first time, amino acid substitutions at positions 3, 5, and 8 of AbA.
• Comparative antifungal activity data for AbA and its new analogs were determined.

Conclusions:

• Novel aureobasidin A analogs with modified amino acid compositions were synthesized.
• Specific amino acid positions in AbA are amenable to substitution, while others (valine-related) are resistant to exogenous replacement.
• The generated analogs and their activity profiles provide valuable insights into AbA's antifungal mechanisms and potential for drug development.