Elucidating Drug Combinations through Bacterial Systems Biology

The spread of antimicrobial resistance has become a serious public health concern, making once treatable diseases deadly again and undermining breakthrough achievements of modern medicine. Drug combinations can aid in fighting multi-drug resistant (MDR) bacterial infections, yet they are largely unexplored and rarely used in clinics. To identify general principles for antibacterial drug combinations and understand their potential, we profiled ˜3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in 6 strains from three Gram-negative pathogens, Escherichia coli, Salmonella Typhimurium and Pseudomonas aeruginosa. Despite their phylogenetic relatedness, more than 70% of the detected drug-drug interactions 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 targeting different cellular processes, whereas synergies are more conserved and enriched in drugs targeting the same process. We elucidate mechanisms underlying this dichotomy and further dissect the interactions of the food additive, vanillin. Finally, we demonstrate that several synergies are effective against MDR clinical isolates in vitro and during infections of Galleria mellonella larvae, with one reverting resistance to the last-resort antibiotic, colistin.