Caenorhabditis elegans has been intensely used as a desirable and efficient model for different genetic and chemical screens. To determine drugs that have a beneficial effect on the immune system, we studied the effect of diverse chemical compounds on the expression of gene F35E12.5, which is a reporter of the activation of the
p38/PMK-1 signaling pathway. Using strain AY101, in which a green fluorescence protein reporter gene was fused to the promoter of gene F35E12.5, we identified 45 compounds which can strongly up-regulate F35E12.5. Sixteen of them are antimicrobial agents, including Quinolones, Azole antifungal agents, Tetracyclines, and Polymyxins. We found that animals treated with antibiotics were more resistant to Y. pestis compared to the untreated ones. In addition, treated animals were also more resistant to control animals when they were infected with antibiotic resistant Y. pestis, indicating that the resistance to infection was not only due to the bactericidal effect of the drug. Our studies identified a new mechanism by which certain antibiotics confer protection to bacterial infections.