The risk ofC. aurisinfection is high because it can colonize the body, resist antifungal treatment, and evade the immune system. The genetic mechanisms for these traits are not well-known. We present an analysis of the genetics and gene expression patterns ofC. auriscarbon metabolism, drug resistance, and macrophage interaction. We chose to study twoC. aurisisolates simultaneously, one drug sensitive (B11220 from Clade II) and one drug resistant (B11221 from Clade III). We found that B11220 was missing a 12.8 kb gene cluster encoding proteins related to alternative sugar utilization, possibly L-rhamnose. We show that B11221 more readily assimilates and utilizes D-galactose and L-rhamnose. B11221 exhibits increased adherence and drug resistance compared to B11220 when grown in these sugars. Transcriptomic analysis of both strains grown on glucose or galactose showed that genes associated with translation were upregulated in B11221. These findings reinforce the growing evidence of a link between metabolism and tolerance. We characterized cell wall composition and macrophage evasion for the two strains. We found that B11221 has far less β-1,3-glucan exposure and resists phagocytosis by macrophages compared to B11220. In a transcriptomic analysis of both strains co-cultured with macrophages we found that B11221 upregulates genes associated with early stages of growth and transcription factors that regulate transport. These key differences in growth and membrane composition could explain the resistance to phagocytosis and increased stress tolerance in general of B11221 and indicates another connection between metabolism and immune system evasion.

We had earlier used Oroidin, a 2‐aminoimidazole‐pyrrole natural microbial biofilm inhibitor, as a structural prototype to develop its 4/5‐acyl modified form as an anti‐biofilm lead for further optimization. Herein, as a part of our efforts towards that direction, we report the design, synthesis, as well as anti‐bacterial, anti‐biofilm, and fungal adhesion inhibition activities of various 4/5‐aroyl‐2‐aminoimidazoles. These simplified Oroidin analogues are moderately active against bacterial biofilms and attest to the need for an aliphatic acyl linker that was part of the original 4/5‐acyl modified Oroidin lead. From our studies, protonation propensity of the 2‐aminoimidazole group of the series emerges as an important pre‐requisite for potent antibiofilm activity. Also, the fungal biofilm screening studies identified analogue 8 b as an active molecule.