c-di-AMP signaling regulates a myriad of physiological processes in Gram-positive bacteria and mycobacteria. c-di-AMP synthase (DAC) is essential in many human pathogens including Staphylococcus aureus, Listeria monocytogenes and Streptococcus pneumoniae and could become an important antibacterial drug target. In our continuing efforts to identify diverse DAC inhibitors, we uncovered hydroxybenzylidene-indolinones as new DAC inhibitors. Interestingly, these compounds also possess antibacterial activities and inhibit biofilm formation. Importantly, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis could be re-sensitized to methicillin and vancomycin, respectively, by hydroxybenzylidene-indolinones.