Project description:<p>Microorganisms maintain metabolic activity in clouds, with recognized impacts on chemical reactivity by contributing to the processing of small organic compounds, radicals and their precursors. However, the conditions in clouds can be highly contrasted (temperature, light, etc), and it remains unknown how these influences microbial metabolism. Here we explored the functioning of microorganisms exposed to typical cloud water conditions through transcriptomics and metabolomics. Mixed cell suspensions of representative microbial isolates from cloud water, composed of a strain of basidiomycetous fungi (Dioszegia hungarica) and three strains of bacteria (Rhodococcus enclensis, Pseudomonas syringae and P. graminis) were prepared in artificial cloud water, and exposed to combined contrasted conditions of temperature (5 vs 17 °C), oxidants (0 vs 250 µM H2O2) and light (dark vs artificial solar light) to mimic cloud conditions during winter night (WN) and summer day (SD). Differential metabolomics and transcriptomics allowed to highlight 25 differently abundant metabolites and 218 differentially expressed genes (DEGs) between these conditions of incubation. In SD: the fungi overexpressed genes of the mitochondrial oxidative phosphorylation chain, fatty acids biosynthesis and succinate assimilation enzymes. the detection by LC-MS of 3 acylcarnitines supports the occurrence of fatty acid transports into the mitochondrion, related with energy production or possibly hydrogen peroxide scavenging. In bacteria, DEGs encoding components of ROS scavenging systems were predominant. In WN: in the yeast, DEGs encoding chaperones, proteins of the ribosome and proteasome were overexpressed, suggesting high protein turnover. For bacteria, protein rescue processes targeting oxidation-sensitive sulphur containing proteins were more expressed, and DL-methionine sulfoxide was detected. Half of the identified bacterial DEG colocalised in 17 clusters suggesting coordinated gene expression. This study demonstrates that eukaryotes and prokaryotes may engage in distinct strategies to survive in clouds depending on environmental conditions.</p>
Project description:Approved drugs are invaluable tools to study biochemical pathways and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here, we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered the synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these two drugs modulates the stability of the androgen receptor (AR) and resensitizes AR mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC might be repurposed to tackle resistance to antiandrogens in prostate cancer patients.