Species-specific activity of antibacterial drug combinations

• Published in: Nature (London) 2018-07, Vol.559 (7713), p.259-263
• Main Authors: Brochado, Ana Rita, Telzerow, Anja, Bobonis, Jacob, Banzhaf, Manuel, Mateus, André, Selkrig, Joel, Huth, Emily, Bassler, Stefan, Zamarreño Beas, Jordi, Zietek, Matylda, Ng, Natalie, Foerster, Sunniva, Ezraty, Benjamin, Py, Béatrice, Barras, Frédéric, Savitski, Mikhail M., Bork, Peer, Göttig, Stephan, Typas, Athanasios
• Format: Article
• Language: English
• Subjects: 49/47; 631/326/22; 631/553/2490; Animals; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiosis; Antibiotics; Antimicrobial agents; Antimicrobial resistance; Bacteria; Bacterial diseases; Bacterial infections; Benzaldehydes - pharmacology; Clinical isolates; Colistin; Colistin - pharmacology; Combination drug therapy; Drug additives; Drug Combinations; Drug dosages; Drug Interactions; Drug resistance; Drug Resistance, Microbial - drug effects; Drug Resistance, Multiple, Bacterial - drug effects; Drug Synergism; Drugs; E coli; Escherichia coli; Escherichia coli - classification; Escherichia coli - drug effects; Experiments; Food additives; Food Additives - pharmacology; Gene expression; Gram-Negative Bacteria - classification; Gram-Negative Bacteria - drug effects; Humanities and Social Sciences; Infection; Integrated approach; Larva - drug effects; Larva - microbiology; Larvae; Letter; Life Sciences; Microbial drug resistance; Microbial Sensitivity Tests; Microbiology and Parasitology; Monoglycerides; Moths; Moths - growth & development; Moths - microbiology; multidisciplinary; Pathogenic microorganisms; Pharmaceutical research; Phylogeny; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa - classification; Pseudomonas aeruginosa - drug effects; Public health; Resorts; Salmonella; Salmonella typhimurium - classification; Salmonella typhimurium - drug effects; Science; Science (multidisciplinary); Species; Species Specificity; Vanillin
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0278-9

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. Screening pairwise combinations of antibiotics and other drugs against three bacterial pathogens reveals that antagonistic and synergistic drug–drug interactions are specific to microbial species and strains.