Antibiotic resistance is a rising health threat worldwide, against which novel strategies are urgently needed. We have taken a systems approach to examine a potent and underexplored class of broad-spectrum antibiotics, the dithiolopyrrolones (DTPs). Our results indicate that DTPs disrupt cellular processes by high-affinity chelation of essential metal ions and inhibition of a subset of metalloenzymes. This mode of action is unique amongst antibiotics and may be further explored for treatment of multidrug-resistant infections. Our study also highlights chemical genomics as a powerful approach for the identification of antimicrobial mechanisms of action
