The increase in antimicrobial resistance is a global health threat, and there is an urgent need to identify new targets and to develop novel antibiotics. In this study, Wang and colleagues used structure-based drug design and modular synthesis to identify small molecules with antimicrobial activity and a reduced propensity for the development of resistance. They found that structure 8 (F8) exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria, including Escherichia coli, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The authors went on to test the in vivo activity of F8 in a mouse sepsis model and showed that the compound effectively reduced the bacterial load in the liver, spleen, kidneys and blood. Moreover, bacteria exposed to sub-inhibitory concentrations of F8 for 30 days developed less resistance compared with bacteria exposed to the antimicrobial drug florfenicol. The authors also showed that treatment with F8 increased the survival rate of mice infected with drug-resistant S. aureus compared with the control, and that bacterial loads were reduced. Using transcriptomics, proteomics and metabolomics the authors found that ornithine carbamoyl transferase (arcB) is the antibacterial target of F8. They report that F8 binds directly to arcB and possibly alters bacterial cell membrane permeability or disrupts cell membrane structure.