Species-specific activity of antibacterial drug combinations

Ana Rita Brochado, Anja Telzerow, Jacob Bobonis, Manuel Banzhaf, André Mateus, Joel Selkrig, Emily Huth, Stefan Bassler, Jordi Zamarreño Beas, Matylda Zietek, Natalie Ng, Sunniva Foerster, Benjamin Ezraty, Béatrice Py, Frédéric Barras, Mikhail M. Savitski, Peer Bork, Stephan Göttig and Athanasios Typas ()
Additional contact information
Ana Rita Brochado: Genome Biology Unit
Anja Telzerow: Genome Biology Unit
Jacob Bobonis: Genome Biology Unit
Manuel Banzhaf: Genome Biology Unit
André Mateus: Genome Biology Unit
Joel Selkrig: Genome Biology Unit
Emily Huth: Hospital of Goethe University
Stefan Bassler: Genome Biology Unit
Jordi Zamarreño Beas: Institut de Microbiologie de la Méditerranée, CNRS UMR 7283, Aix-Marseille Université
Matylda Zietek: Genome Biology Unit
Natalie Ng: Stanford University
Sunniva Foerster: University of Bern
Benjamin Ezraty: Institut de Microbiologie de la Méditerranée, CNRS UMR 7283, Aix-Marseille Université
Béatrice Py: Institut de Microbiologie de la Méditerranée, CNRS UMR 7283, Aix-Marseille Université
Frédéric Barras: Institut de Microbiologie de la Méditerranée, CNRS UMR 7283, Aix-Marseille Université
Mikhail M. Savitski: Genome Biology Unit
Peer Bork: European Molecular Biology Laboratory, Structural & Computational Biology Unit
Stephan Göttig: Hospital of Goethe University
Athanasios Typas: Genome Biology Unit

Nature, 2018, vol. 559, issue 7713, 259-263

Abstract: Abstract The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine1,2. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0278-9

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