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Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug

Petra Szili, Gábor Draskovits, Tamás Révész, Ferenc Bogar, Dávid Balogh, Tamás Martinek, Lejla Daruka, Réka Spohn, Bálint Márk Vásárhelyi, Márton Czikkely, Bálint Kintses, Gábor Grézal, Györgyi Ferenc, Csaba Pál, View ORCID ProfileÁkos Nyerges
doi: https://doi.org/10.1101/495630
Petra Szili
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
6Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary
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Gábor Draskovits
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Tamás Révész
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
5Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary
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Ferenc Bogar
2MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary
3Department of Medical Chemistry, University of Szeged, Szeged, Hungary
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Dávid Balogh
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Tamás Martinek
3Department of Medical Chemistry, University of Szeged, Szeged, Hungary
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Lejla Daruka
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Réka Spohn
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Bálint Márk Vásárhelyi
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Márton Czikkely
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
7Szeged Scientists Academy, Szeged, Hungary
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Bálint Kintses
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Gábor Grézal
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Györgyi Ferenc
4Nucleic Acid Synthesis Laboratory, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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Csaba Pál
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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  • For correspondence: nyerges.akos@brc.mta.hu pal.csaba@brc.mta.hu
Ákos Nyerges
1Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary
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  • ORCID record for Ákos Nyerges
  • For correspondence: nyerges.akos@brc.mta.hu pal.csaba@brc.mta.hu
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Abstract

Multi-targeting antibiotics, i.e. single compounds capable to inhibit two or more bacterial targets offer a promising therapeutic strategy, but information on resistance evolution against such drugs is scarce. Gepotidacin is an antibiotic candidate that selectively inhibits both bacterial DNA gyrase and topoisomerase IV. In a susceptible organism, Klebsiella pneumoniae, a combination of two specific mutations in these target proteins provide an over 2000-fold increment in resistance, while individually none of these mutations affect resistance significantly. Alarmingly, gepotidacin-resistant strains are found to be as virulent as the wild-type K. pneumoniae strain in a murine model, and extensive cross-resistance was demonstrated between gepotidacin and ciprofloxacin, a fluoroquinolone antibiotic widely employed in clinical practice. This suggests that numerous fluoroquinolone-resistant pathogenic isolates carry mutations which would promote the evolution of clinically significant resistance against gepotidacin in the future. We conclude that prolonged antibiotic usage could select for mutations that serve as stepping-stones towards resistance against antimicrobial compounds still under development. More generally, our research indicates that even balanced multi-targeting antibiotics are prone to resistance evolution.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted December 13, 2018.
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Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug
Petra Szili, Gábor Draskovits, Tamás Révész, Ferenc Bogar, Dávid Balogh, Tamás Martinek, Lejla Daruka, Réka Spohn, Bálint Márk Vásárhelyi, Márton Czikkely, Bálint Kintses, Gábor Grézal, Györgyi Ferenc, Csaba Pál, Ákos Nyerges
bioRxiv 495630; doi: https://doi.org/10.1101/495630
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Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug
Petra Szili, Gábor Draskovits, Tamás Révész, Ferenc Bogar, Dávid Balogh, Tamás Martinek, Lejla Daruka, Réka Spohn, Bálint Márk Vásárhelyi, Márton Czikkely, Bálint Kintses, Gábor Grézal, Györgyi Ferenc, Csaba Pál, Ákos Nyerges
bioRxiv 495630; doi: https://doi.org/10.1101/495630

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