Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections.

Interfering with sterol biosynthesis is an important strategy for developing safe and effective antifungal drugs. We previously identified compound H55 as an allosteric inhibitor of the fungal-specific C-24 sterol methyltransferase Erg6 for treating Candida albicans infections. Herein, 62 derivatives of H55 were designed and synthesized based on target-ligand interactions to identify more active candidates. Among them, d28 displayed the most potent antivirulence ability (MHIC50 = 0.25 µg/mL) by targeting Erg6, exhibiting an 8-fold increase in potency compared with H55. Moreover, d28 significantly outperformed H55 in inhibiting cell adhesion and biofilm formation, and exhibited minimal cytotoxicity and negligible potential to induce drug resistance. Of note, the coadministration of d28 and other sterol biosynthesis inhibitors, such as tridemorph or terbinafine, demonstrated a strong synergistic antifungal action in vitro and in vivo in a murine skin infection model. These results support the potential application of d28 in the treatment of C. albicans infections.

Land cover alteration shifts ecological assembly processes in floodplain lakes: Consequences for fish community dynamics.

Habitat degradation is expected to alter community structure and consequently, ecosystem functions including the maintenance of biodiversity. Understanding the underlying abiotic and biotic assembly mechanisms controlling temporal and spatial community structure and patterns is a central issue in biodiversity conservation. In this study, using monthly time series of fish abundance data collected over a three-year period, we compared the temporal community dynamics in natural habitats and poplar plantations in one of the largest river-lake floodplain ecosystems in China, the Dongting Lake. We found a prevailing strong positive species covariance, i.e. species abundance changes in the same way, in all communities that was significantly negatively impacted by higher water nutrient levels. In contrast to species covariance, community stability, which was measured by the average of aggregated abundance divided by temporal standard deviation, was significantly higher in poplar plantations than in natural habitats. The positive species covariance, which was consistent for both wet and dry years and among habitat types, had significantly negative effects on community stability. Furthermore, our results demonstrated that the ecological stochasticity (i.e. community assembly processes generating diversity patterns that are indistinguishable from random chance) was significantly higher in natural sites than in poplar plantations, suggesting that deterministic processes might control the community composition (richness and abundance) at the modified habitat through reducing species synchrony and positive species covariance observed in the natural habitats, leading to significantly lower temporal ß-diversity. When combined, our results suggest that habitat modification created environmental conditions for the development of stable fish community in the highly dynamic floodplains, leading to niche-based community with lower temporal ß-diversity.

Lake productivity and waterbird functional diversity across geographic and environmental gradients in temperate China.

Geographical gradients in species diversity have long fascinated biogeographers and ecologists. However, the extent and generality of the effects of the important factors governing functional diversity (FD) patterns are still debated, especially for the freshwater domain. We examined the relationship between lake productivity and functional diversity of waterbirds sampled from 35 lakes and reservoirs in northern China with a geographic coverage of over 5 million km2. We used structural equation modeling (SEM) to explore the causal relationships between geographic position, climate, lake productivity, and waterbird FD. We found unambiguous altitudinal and longitudinal gradients in lake productivity and waterbird FD, which were strongly mediated by local environmental factors. Specifically, we found (a) lake productivity increased northeast and decreased with altitude. The observed geographic and altitudinal gradients were driven by climatic conditions and nutrient availability, which collectively explained 93% of the variations in lake productivity; (b) waterbird FD showed similar geographic and altitudinal gradients; the environmental factors which had direct and/or indirect effects on these gradients included climate and lake area, which collectively explained more than 39% of the variation in waterbird FD; and 3) a significant (p = .029) causality between lake productivity and waterbird FD was confirmed. Nevertheless, the causality link was relatively weak in comparison with climate and lake area (the standardized path coefficient was 0.55, 0.23, and 0.03 for climate, lake area, and productivity, respectively). Our study demonstrates how the application of multivariate technique (e.g., SEM) enables the illustration of complex causal paths in ecosystems, enhancing mechanistic explanations that underlie the observed broadscale biodiversity gradients.