An oligosaccharide analog exhibited antifungal activity by misleading cell wall organization via targeting PHR transglucosidases

The fungal cell wall is an ideal target for the design of antifungal drugs. In this study we used an analog of cell wall polymer, a highly deacetylated long-chain chitosan oligosaccharide (HCOS), to test its effect against pathogenic Candida strains. Results showed that HCOS was successfully incorporated into the dynamic cell wall organization process and exhibited an apparent antifungal activity against both plankton and mature fungal biofilm, by impairing the cell wall integrity. Unexpectedly, mechanistic studies suggested that HCOS exerts its activity by interfering with family members of PHR {beta}-(1,3)-glucanosyl transferases and affecting the connection and assembly of cell wall polysaccharides. Furthermore, HCOS showed great synergistic activity with different fungicides against Candida cells, especially those in biofilm. These findings indicated HCOS has a great potential as an antifungal drug or drug synergist and proposed a novel antifungal strategy with structure-specific oligosaccharides mimicking cell wall polysaccharide fragments. IMPORTANCEFungal infections have always been a puzzle in clinical medicine. Only a few antifungal drugs are available for medical usage and the widespread use of antifungal drugs increased the incidence of drug resistance. It is an urgent need for the development of novel treatment strategies against fungal infections. In this study, we proposed a novel strategy targeting to fungal cell wall against C. albicans. To our knowledge, it is the first study to show a cell wall polysaccharide fragment analog integrate into and interfere with the fungal cell wall, indicating a novel antifungal strategy using structure-specific oligosaccharides mimicking cell wall polysaccharide fragments.