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Inhibiting the copper efflux system in microbes as a novel approach for developing antibiotics

Aviv Meir, Veronica Lepechkin-Zilbermintz, Shirin Kahremany, Fabian Schwerdtfeger, Lada Gevorkyan-Airapetov, Anna Munder, Olga Viskind, Arie Gruzman, View ORCID ProfileSharon Ruthstein
doi: https://doi.org/10.1101/763185
Aviv Meir
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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Veronica Lepechkin-Zilbermintz
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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Shirin Kahremany
2Gavin Herbert Eye Institute and the Department of Ophthalmology, University of California, Irvine, California, USA 92697
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Fabian Schwerdtfeger
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
3Faculty of Biology, Albert-Ludwigs-University Freiburg, Centre for Biological Signaling Studies (BIOSS), Schänzlestraße 18, 79104, Freiburg, Germany
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Lada Gevorkyan-Airapetov
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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Anna Munder
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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Olga Viskind
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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Arie Gruzman
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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  • For correspondence: Sharon.ruthstein@biu.ac.il gruzmaa@biu.ac.il
Sharon Ruthstein
1Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, 5290002, Israel
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  • ORCID record for Sharon Ruthstein
  • For correspondence: Sharon.ruthstein@biu.ac.il gruzmaa@biu.ac.il
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Abstract

Five out of six people receive at least one antibiotic prescription per year. However, the ever-expanding use of antibiotics in medicine, agriculture, and food production has accelerated the evolution of antibiotic-resistant bacteria, which, in turn, made the development of novel antibiotics based on new molecular targets a priority in medicinal chemistry. One way of possibly combatting resistant bacterial infections is by inhibiting the copper transporters in prokaryotic cells. Copper is a key element within all living cells, but it can be toxic in excess. Both eukaryotic and prokaryotic cells have developed distinct copper regulation systems to prevent its toxicity. Therefore, selectively targeting the prokaryotic copper regulation system might be an initial step in developing next-generation antibiotics. One such system is the Gram-negative bacterial CusCFBA efflux system. CusB is a key protein in this system and was previously reported to play an important role in opening the channel for efflux via significant structural changes upon copper binding while also controlling the assembly and disassembly process of the entire channel. In this study, we aimed to develop novel peptide copper channel blockers, designed by in silico calculations based on the structure of CusB. Using a combination of magnetic resonance spectroscopy and various biochemical methods, we found a lead peptide that promotes copper-induced cell toxicity. Targeting copper transport in bacteria has not yet been pursued as an antibiotic mechanism of action. Thus, our study lays the foundation for discovering novel antibiotics.

Author Summary Herein, we apply a novel approach for the development of a new generation of antibiotics based on copper toxicity. In cells, copper ions are double-edge swords. On the one hand, various enzymes depend on them as cofactors for catalysis, but on the other hand, they are highly toxic. Thus, cells have developed sophisticated regulation systems to very precisely control copper concentration. Prokaryotic organisms are more sensitive to copper than eukaryotic systems, and therefore they employ additional copper transporters that have no homology in the eukaryotic cells in general and specifically in the human cell. Here, we suggest to take advantage of this fact, by developing inhibitors against one of the bacterial copper transporter: CusCBA. The adaptor protein within this transporter, CusB, plays a critical role in the opening of the whole transporter. We designed a peptide that interfere with its proper function and assembly, and therefore inhibits the opening of the transporter upon copper stress. This study lays the foundation for designing better and novel antibiotics.

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  • Conflicts of Interest: The authors declare that they have no conflicts of interest with the contents of this article

Copyright 
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 4.0 International license.
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Posted September 09, 2019.
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Inhibiting the copper efflux system in microbes as a novel approach for developing antibiotics
Aviv Meir, Veronica Lepechkin-Zilbermintz, Shirin Kahremany, Fabian Schwerdtfeger, Lada Gevorkyan-Airapetov, Anna Munder, Olga Viskind, Arie Gruzman, Sharon Ruthstein
bioRxiv 763185; doi: https://doi.org/10.1101/763185
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Inhibiting the copper efflux system in microbes as a novel approach for developing antibiotics
Aviv Meir, Veronica Lepechkin-Zilbermintz, Shirin Kahremany, Fabian Schwerdtfeger, Lada Gevorkyan-Airapetov, Anna Munder, Olga Viskind, Arie Gruzman, Sharon Ruthstein
bioRxiv 763185; doi: https://doi.org/10.1101/763185

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