The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine^1,2. Drug combinations can help to fight multi-drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens—Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa—to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug–drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth Galleria mellonella, with one reverting resistance to the last-resort antibiotic colistin.

Unreactive Death: A controversial proposal that all bactericidal antibiotics kill by reactive oxygen species (ROS) and not by their primary cell target has recently attracted high-profile refutations. The ROS-death pathway implicated overstimulation of the electron transport in respiratory chains; a malfunction that leads to ROS releasing Fe from Fe-S clusters and causing cell death via Fenton chemistry. Ezraty et al. (p. 1583 ) show that electron transport chains and Fe-S clusters are key to killing by aminoglycoside antibiotics but not for the reasons envisioned in the ROS theory. Fe-S clusters are essential for killing because they mature the respiratory chains that produce the necessary proton motive force for the energized uptake of aminoglycosides. Consequently, iron chelators protect against aminoglycosides, not because they scavenge the iron from Fenton chemistry, but because they block aminoglycoside uptake.

Proteins containing [Fe—S] clusters perform essential functions in all domains of life. Previously, we identified the sufABCDSE operon as being necessary for virulence of the plant pathogen Erwinia chrysanthemi . In addition, we collected preliminary evidence that the sufABCDSE operon might be involved in the assembly of [Fe—S] clusters. Of particular interest are the sufB, sufC and sufD genes, which are conserved among Eubacteria, Archaea, plants and parasites. The present study establishes SufC as an unorthodox ATPase of the ABC superfamily that is located in the cytosol, wherein it interacts with both SufB and SufD. Moreover, under oxidative stress conditions, SufC was found to be necessary for the activity of enzymes containing oxygen‐labile [Fe—S] clusters, but dispensable for glutamate synthase, which contains an oxidatively stable [Fe—S] cluster. Lastly, we have shown SufBCD to be essential for iron acquisition via chrysobactin, a siderophore of major importance in virulence. We discuss a model wherein the SufBCD proteins contribute to bacterial pathogenicity via their role in the assembly of [Fe—S] clusters under oxidative stress and iron limitation.