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Dissecting the collateral damage of antibiotics on gut microbes

Lisa Maier, Camille V. Goemans, Mihaela Pruteanu, Jakob Wirbel, Michael Kuhn, Elisabetta Cacace, Tisya Banerjee, Exene Erin Anderson, Alessio Milanese, Ulrike Löber, Sofia K. Forslund, Kiran Raosaheb Patil, Georg Zeller, Peer Bork, Athanasios Typas
doi: https://doi.org/10.1101/2020.01.09.893560
Lisa Maier
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
7Interfaculty Institute of Microbiology & Infection Medicine Tübingen, Germany
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  • For correspondence: typas@embl.de l.maier@uni-tuebingen.de
Camille V. Goemans
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
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Mihaela Pruteanu
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
8Institute for Biology, Humboldt University Berlin, Germany
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Jakob Wirbel
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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Michael Kuhn
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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Elisabetta Cacace
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
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Tisya Banerjee
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
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Exene Erin Anderson
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
9NYU School of Medicine, New York, USA
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Alessio Milanese
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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Ulrike Löber
3Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany
4Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
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Sofia K. Forslund
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
3Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany
4Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
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Kiran Raosaheb Patil
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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Georg Zeller
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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Peer Bork
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
4Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
5Molecular Medicine Partnership Unit, Heidelberg, Germany
6Department of Bioinformatics, Biocenter, University of Würzburg, Germany
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Athanasios Typas
1European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
2European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
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  • For correspondence: typas@embl.de l.maier@uni-tuebingen.de
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Abstract

Antibiotics are used for fighting pathogens, but also target our commensal bacteria as a side effect, disturbing the gut microbiota composition and causing dysbiosis and disease1-3. Despite this well-known collateral damage, the activity spectrum of the different antibiotic classes on gut bacteria remains poorly characterized. Having monitored the activities of >1,000 marketed drugs on 38 representative species of the healthy human gut microbiome4, we here characterize further the 144 antibiotics therein, representing all major classes. We determined >800 Minimal Inhibitory Concentrations (MICs) and extended the antibiotic profiling to 10 additional species to validate these results and link to available data on antibiotic breakpoints for gut microbes. Antibiotic classes exhibited distinct inhibition spectra, including generation-dependent effects by quinolones and phylogeny-independence by β-lactams. Macrolides and tetracyclines, two prototypic classes of bacteriostatic protein synthesis inhibitors, inhibited almost all commensals tested. We established that both kill different subsets of prevalent commensal bacteria, and cause cell lysis in specific cases. This species-specific activity challenges the long-standing divide of antibiotics into bactericidal and bacteriostatic, and provides a possible explanation for the strong impact of macrolides on the gut microbiota composition in animals5-8 and humans9-11. To mitigate the collateral damage of macrolides and tetracyclines on gut commensals, we exploited the fact that drug combinations have species-specific outcomes in bacteria12 and sought marketed drugs, which could antagonize the activity of these antibiotics in abundant gut commensal species. By screening >1,000 drugs, we identified several such antidotes capable of protecting gut species from these antibiotics without compromising their activity against relevant pathogens. Altogether, this study broadens our understanding of antibiotic action on gut commensals, uncovers a previously unappreciated and broad bactericidal effect of prototypical bacteriostatic antibiotics on gut bacteria, and opens avenues for preventing the collateral damage caused by antibiotics on human gut commensals.

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Posted January 09, 2020.
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Dissecting the collateral damage of antibiotics on gut microbes
Lisa Maier, Camille V. Goemans, Mihaela Pruteanu, Jakob Wirbel, Michael Kuhn, Elisabetta Cacace, Tisya Banerjee, Exene Erin Anderson, Alessio Milanese, Ulrike Löber, Sofia K. Forslund, Kiran Raosaheb Patil, Georg Zeller, Peer Bork, Athanasios Typas
bioRxiv 2020.01.09.893560; doi: https://doi.org/10.1101/2020.01.09.893560
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Dissecting the collateral damage of antibiotics on gut microbes
Lisa Maier, Camille V. Goemans, Mihaela Pruteanu, Jakob Wirbel, Michael Kuhn, Elisabetta Cacace, Tisya Banerjee, Exene Erin Anderson, Alessio Milanese, Ulrike Löber, Sofia K. Forslund, Kiran Raosaheb Patil, Georg Zeller, Peer Bork, Athanasios Typas
bioRxiv 2020.01.09.893560; doi: https://doi.org/10.1101/2020.01.09.893560

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