Abstract
Bacteria and fungi can secrete and reside within a complex polysaccharide matrix, forming a biofilm that protects these pathogens from the immune response and conventional antibiotics. Because many microbial pathogens grow within biofilms in clinical settings, there is a need for antimicrobial agents effective against biofilm-protected infections. We report the adaptation of a phenotypic high-throughput assay for discovering antimicrobial peptoids toward the screening of combinatorial libraries against established biofilms. This method, termed the Inverted Peptoid Library Agar Diffusion (iPLAD) assay, required optimization of growth media, reducing reagent, and fungal viability reporter. Once optimized, iPLAD was used to screen a combinatorial peptoid library against Candida albicans, a biofilm-forming fungal pathogen responsible for most hospital-acquired infections. This screening resulted in a lipopeptoid termed RMG9-11 with excellent activity against several species of Candida, including drug-resistant strains of C. albicans and the emerging and dangerous C. auris. Additionally, the cytotoxicity of RMG9-11 against several mammalian cell lines was minimal. This work provides a new method for the identification of compounds effective against biofilm-protected pathogens and demonstrates its utility by identifying a promising anti-Candida peptoid.