Abstract
In the course of optimizing GPI biosynthesis inhibitors, we designed and synthetized a 2-aminonicotinamide derivative named 11g. After evaluating the antifungal activity of compound 11g in vitro, we investigated the influences of 11g on fungi immunogenicity. In addition, we also took advantage of murine systemic candidiasis model to investigate the protective effects of 11g in vivo. Results show that 11g exhibited potent antifungal activity both in vitro and in vivo. Further study shows that 11g caused the unmasking of fungi β-glucan layer, leading to stronger immune responses in macrophages through Dectin-1. These results suggest that 11g is a very promising antifungal candidate, which assists in eliciting stronger immune responses to help host immune system disposing pathogens. The discovery of 11g might expand the toolbox of fungal infection treatment.
Highlights
Fungi are encountered, ingested, and inhaled by human beings every day
In order to expand the antifungal spectrum of 11g, we investigated the antifungal activity of 11g against 17 clinical isolates of Candida species
As we found out that 11g can unmask the β-(1, 3)-glucan, we reasoned that 11g can enhance the immunogenicity of C. albicans, leading to the boost of innate immune cell responses (Brown et al, 2003; Gantner et al, 2003; Netea et al, 2008)
Summary
Fungi are encountered, ingested, and inhaled by human beings every day. As opportunistic pathogens, their infection spectrum ranges from benignly superficial colonization to systemic fungal infection. As a result of the increasing number of susceptible immunocompromised and immunosuppressed patients, the incidence rate of clinically relevant fungal infections has risen steadily in the past three to four decades (LeibundGut-Landmann et al, 2012; McLellan et al, 2012). Candida species, which caused mostly fungus-related morbidity and mortality, are the fourth leading cause of hospital-acquired bloodstream infections (Cowen et al, 2002). There are between 1.1 and 24 cases of candidemia per 100,000 individuals, killing more than 30% of their victims (Gudlaugsson et al, 2003; Wisplinghoff et al, 2004)
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