Oncotarget

Research Papers:

Mitoriboscins: Mitochondrial-based therapeutics targeting cancer stem cells (CSCs), bacteria and pathogenic yeast

Bela Ozsvari, Marco Fiorillo, Gloria Bonuccelli, Anna Rita Cappello, Luca Frattaruolo, Federica Sotgia, Rachel Trowbridge, Richard Foster, Michael P. Lisanti _

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Oncotarget. 2017; 8:67457-67472. https://doi.org/10.18632/oncotarget.19084

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Abstract

Bela Ozsvari1,2, Marco Fiorillo1,2,3, Gloria Bonuccelli1,2, Anna Rita Cappello3, Luca Frattaruolo3, Federica Sotgia1,2, Rachel Trowbridge5, Richard Foster4,5 and Michael P. Lisanti1,2

1 Translational Medicine, School of Environment & Life Sciences, University of Salford, Greater Manchester, UK

2 The Paterson Institute, University of Manchester, Withington, UK

3 The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy

4 Astbury Centre for Structural Molecular Biology, University of Leeds, West Yorkshire, UK

5 School of Chemistry, Faculty of Mathematics and Physical Sciences, University of Leeds, West Yorkshire, UK

Correspondence to:

Michael P. Lisanti, email:

Richard Foster, email:

Keywords: antibiotic, drug design, mitochondrial ribosome, mitoribosome, mitochondria

Received: April 02, 2017 Accepted: May 17, 2017 Published: July 07, 2017

Abstract

The “endo-symbiotic theory of mitochondrial evolution” states that mitochondrial organelles evolved from engulfed aerobic bacteria, after millions of years of symbiosis and adaptation. Here, we have exploited this premise to design new antibiotics and novel anti-cancer therapies, using a convergent approach. First, virtual high-throughput screening (vHTS) and computational chemistry were used to identify novel compounds binding to the 3D structure of the mammalian mitochondrial ribosome. The resulting library of ~880 compounds was then subjected to phenotypic drug screening on human cancer cells, to identify which compounds functionally induce ATP-depletion, which is characteristic of mitochondrial inhibition. Notably, the top ten “hit” compounds define four new classes of mitochondrial inhibitors. Next, we further validated that these novel mitochondrial inhibitors metabolically target mitochondrial respiration in cancer cells and effectively inhibit the propagation of cancer stem-like cells in vitro. Finally, we show that these mitochondrial inhibitors possess broad-spectrum antibiotic activity, preventing the growth of both gram-positive and gram-negative bacteria, as well as C. albicans - a pathogenic yeast. Remarkably, these novel antibiotics also were effective against methicillin-resistant Staphylococcus aureus (MRSA). Thus, this simple, yet systematic, approach to the discovery of mitochondrial ribosome inhibitors could provide a plethora of anti-microbials and anti-cancer therapies, to target drug-resistance that is characteristic of both i) tumor recurrence and ii) infectious disease. In summary, we have successfully used vHTS combined with phenotypic drug screening of human cancer cells to identify several new classes of broad-spectrum antibiotics that target both bacteria and pathogenic yeast. We propose the new term “mitoriboscins” to describe these novel mitochondrial-related antibiotics. Thus far, we have identified four different classes of mitoriboscins, such as: 1) mitoribocyclines, 2) mitoribomycins, 3) mitoribosporins and 4) mitoribofloxins. However, we broadly define mitoriboscins as any small molecule(s) or peptide(s) that bind to the mitoribosome (large or small subunits) and, as a consequence, inhibit mitochondrial function, i.e., mitoribosome inhibitors.


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