Classical antibiotics target vital cell functions,but this strategy has led to the development of multi-resistant microbes and we are running out of options to cure such infections.Therefore,novel solutions are needed and we have pursued an alternative strategy:to discover small molecules that specifically target bacterial virulence functions (1).The rationale for this approach is that the inhibition of virulence functions will essentially disarm the bacteria,so that they can be cleared from the body by immune system action.Our model is that of bacterial type Ⅳ secretion systems (T4SS),membrane-associated multiprotein complexes that mediate the translocation of virulence factors across the bacterial cell envelope.They are required for the virulence of many bacterial pathogens and therefore constitute interesting targets for the development of anti-virulence drugs (2).We study the mechanism of T4SS using the plant pathogen Agrobacterium tumefaciens and the mammalian pathogen Brucella suis as models.We will present the results of our work using protein biochemical,structural biological and chemical biology approaches (3,4).Based on the crystal structure of the essential T4SS component VirB8 we identified residues that are essential for the functionality of the protein using in vivo as well as in vitro assays.We established a cell-based VirB8 interaction assay and high-throughput screening identified small-molecule inhibitors that inhibit bacterial virulence.In future,we will apply small organic molecules as probes for the analysis of the mechanism of the translocation process and they may also serve as leads for the development of anti-virulence drugs.