Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

摘要: Abstract Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, feasibility of this approach is beginning to wane and attention has begun shift toward disrupting host-pathogen interaction by improving host defense. Using a high-throughput, fragment-based screen identify compounds that alleviate Pseudomonas aeruginosa-mediated Caenorhabditis elegans, we identified over 20 stimulated defense gene expression. Five these molecules were selected further characterization. Four five showed little toxicity against mammalian cells worms, consistent with their identification in phenotypic, high-content screen. Each activated several pathways, but pathways generally dispensable compound-mediated rescue Liquid Killing, suggesting redundancy activation one unknown may be driving compound effects. A genetic mechanism was LK56, which required Mediator subunit MDT-15/MED15 NHR-49/HNF4 function. Interestingly, LK32, LK34, LK38, LK56 also C. elegans from P. aeruginosa an agar-based assay, uses different virulence factors mechanisms. Rescue assay LK38 entirely depended upon PMK-1/p38 MAPK pathway. Three compounds, conferred Enterococcus faecalis, two lattermost, LK34 reduced pathogenesis Staphylococcus aureus. This study supports growing role MDT-15 NHR-49 immune response identifies 5 significant potential use as tools investigation innate immunity. Author Summary Two trends moving opposite directions (the increase decline commercial interest discovery development novel antimicrobials) precipitated looming crisis: nearly complete inability safely effectively treat infections. To avert this, new approaches healthcare are needed. One receiving increasing stimulate improve clearance We describe small promote infectious bacteria, at least partially activating elegans’ pathways. Several effective both Gram-positive Gram-negative pathogens. molecules, LK35, highly overlapping downstream target genes, they act common despite having distinct chemical structures. mapped action NHR-49/HNF4, pair transcriptional regulators associated fatty acid metabolism, potentially highlighting link between biological functions. These studies pave way future characterization anti-infective activity higher organisms highlight compounds’ utility modulation therapeutic approach.