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


Autoři: Aviv Meir aff001;  Veronica Lepechkin-Zilbermintz aff001;  Shirin Kahremany aff002;  Fabian Schwerdtfeger aff001;  Lada Gevorkyan-Airapetov aff001;  Anna Munder aff001;  Olga Viskind aff001;  Arie Gruzman aff001;  Sharon Ruthstein aff001
Působiště autorů: Chemistry Department, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan, Israel aff001;  Gavin Herbert Eye Institute and the Department of Ophthalmology, University of California, Irvine, California, United States of America aff002;  Faculty of Biology, Albert-Ludwigs-University Freiburg, Centre for Biological Signaling Studies (BIOSS), Freiburg, Germany aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0227070

Souhrn

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.

Klíčová slova:

Antibiotic resistance – Antibiotics – Bacterial diseases – Crystal structure – Deer – Dimers – Electron spin resonance spectroscopy – Periplasm


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