Previously Uncharacterized Variants, OCF-E-OCF-J, of the Antifungal Occidiofungin Produced by Burkholderia...

Area of Science:

• Biochemistry
• Microbiology
• Medicinal Chemistry

Background:

• Multidrug resistant fungal infections pose a significant global health threat, necessitating the development of new antifungal agents.
• Occidiofungin, a unique glycolipopeptide, exhibits antifungal activity by disrupting actin and inducing apoptosis.
• Previous studies identified an asparagine residue at position 7 (ASN7) in occidiofungin.

Purpose of the Study:

• To characterize new structural variants of occidiofungin with different amino acids at position 7.
• To synthesize and evaluate semi-synthetic analogues based on the aspartic acid variant (ASP7) for enhanced antifungal activity.
• To explore the therapeutic potential of occidiofungin variants for combating resistant fungal infections.

Main Methods:

• Characterization of occidiofungin variants with aspartic acid (ASP7), glutamine (GLN7), and glutamic acid (GLU7) at position 7.
• Synthesis of semi-synthetic analogues by chemically modifying the ASP7 variant.
• In vitro testing of antifungal activity against a panel of Candida species.

Main Results:

• Structural variants with ASP7, GLN7, and GLU7 at position 7 were identified.
• The ASP7 variant, featuring a terminal carboxylic acid, served as a key site for chemical modification.
• Synthesized analogues based on the ASP7 variant demonstrated superior antifungal activity compared to the ASP7 variant itself against various Candida species.

Conclusions:

• Occidiofungin variants with a carboxylic acid at the seventh amino acid position are promising for developing improved antifungal therapies.
• Semi-synthetic modification of occidiofungin at the ASP7 position can yield analogues with enhanced therapeutic properties.
• These findings contribute to the search for novel treatments against multidrug resistant fungal infections, including Candida auris.