Semi-rational Strategies for Antifungal Peptide Design

A recently emerged opportunistic fungi, Candida auris, has been subject to increased scrutiny due to its virulence and rapid geographical spread. Due to the indiscriminate use of antimicrobials as treatments for infectious diseases and as pesticides, the ubiquitous threat of multidrug resistance (MDR) looms large. The lack of progress in antifungal development is of high concern in the treatment of infectious diseases and a rise in fungal resistance highlight the need for updated treatment strategies. This work describes three strategies used to address these concerns: The synthesis of a photosensitizer-membrane-active peptide (PS-MAP) conjugate, Ir-HKII15, that combines the ability of photosensitizers to produce membrane-damaging reactive oxygen species (ROS) with the destabilizing effects associated with membrane-active peptides (MAPs); The design of a combinatorial peptide library that incorporates the well-studied ATCUN (amino terminal copper and nickel) binding motif into a translocating peptide sequence, TP2; and Combining the benefits of rational design and combinatorial libraries while avoiding the limitations of introducing single amino acid modifications and allows for direct microbiological testing.