2. Academic Validation
  3. Species-specific activity of antibacterial drug combinations

Species-specific activity of antibacterial drug combinations

  • Nature. 2018 Jul;559(7713):259-263. doi: 10.1038/s41586-018-0278-9.
Ana Rita Brochado 1,  Anja Telzerow 1,  Jacob Bobonis 1,  Manuel Banzhaf 1 2,  André Mateus 1,  Joel Selkrig 1,  Emily Huth 3,  Stefan Bassler 1,  Jordi Zamarreño Beas 4,  Matylda Zietek 1,  Natalie Ng 5,  Sunniva Foerster 6,  Benjamin Ezraty 4,  Béatrice Py 4,  Frédéric Barras 4 7,  Mikhail M Savitski 1,  Peer Bork 8 9 10 11,  Stephan Göttig 3,  Athanasios Typas 12 13
Affiliations

Affiliations

  • 1 European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
  • 2 Institute of Microbiology & Infection, School of Biosciences, University of Birmingham, Birmingham, UK.
  • 3 Institute of Medical Microbiology and Infection Control, Hospital of Goethe University, Frankfurt am Main, Germany.
  • 4 Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, CNRS UMR 7283, Aix-Marseille Université, Marseille, France.
  • 5 Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 6 Institute of Social & Preventive Medicine, Institute of Infectious Diseases, University of Bern, Bern, Switzerland.
  • 7 Institut Pasteur, Paris, France.
  • 8 European Molecular Biology Laboratory, Structural & Computational Biology Unit, Heidelberg, Germany.
  • 9 Max-Delbrück-Centre for Molecular Medicine, Berlin, Germany.
  • 10 Molecular Medicine Partnership Unit, Heidelberg, Germany.
  • 11 Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
  • 12 European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany. [email protected].
  • 13 European Molecular Biology Laboratory, Structural & Computational Biology Unit, Heidelberg, Germany. [email protected].
PMID: 29973719 DOI: 10.1038/s41586-018-0278-9
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.

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