Species-specific activity of antibacterial drug combinations

Item Type:	Article
Title:	Species-specific activity of antibacterial drug combinations
Creators Name:	Brochado, A.R. and Telzerow, A. and Bobonis, J. and Banzhaf, M. and Mateus, A. and Selkrig, J. and Huth, E. and Bassler, S. and Zamarreño Beas, J. and Zietek, M. and Ng, N. and Foerster, S. and Ezraty, B. and Py, B. and Barras, F. and Savitski, M.M. and Bork, P. and Göttig, S. and Typas, A.
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 medicine. 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.
Keywords:	Anti-Bacterial Agents, Benzaldehydes, Colistin, Drug Combinations, Drug Interactions, Drug Synergism, Escherichia Coli, Food Additives, Gram-Negative Bacteria, Microbial, Drug Resistance, Multiple, Drug Resistance, Bacterial, Microbial Sensitivity Tests, Phylogeny, Pseudomonas Aeruginosa, Species Specificity, Animals, Larva, Moths
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	559
Number:	7713
Page Range:	259-263
Date:	July 2018
Official Publication:	https://doi.org/10.1038/s41586-018-0278-9
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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