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Rapid Inhibitor Discovery by Exploiting Synthetic Lethality

[Image: see text] Synthetic lethality occurs when inactivation of two genes is lethal but inactivation of either single gene is not. This phenomenon provides an opportunity for efficient compound discovery. Using differential growth screens, one can identify biologically active compounds that select...

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Autores principales: Muscato, Jacob D., Morris, Heidi G., Mychack, Aaron, Rajagopal, Mithila, Baidin, Vadim, Hesser, Anthony R., Lee, Wonsik, İnecik, Kemal, Wilson, Laura J., Kraml, Christina M., Meredith, Timothy C., Walker, Suzanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012225/
https://www.ncbi.nlm.nih.gov/pubmed/35170959
http://dx.doi.org/10.1021/jacs.1c12697
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author Muscato, Jacob D.
Morris, Heidi G.
Mychack, Aaron
Rajagopal, Mithila
Baidin, Vadim
Hesser, Anthony R.
Lee, Wonsik
İnecik, Kemal
Wilson, Laura J.
Kraml, Christina M.
Meredith, Timothy C.
Walker, Suzanne
author_facet Muscato, Jacob D.
Morris, Heidi G.
Mychack, Aaron
Rajagopal, Mithila
Baidin, Vadim
Hesser, Anthony R.
Lee, Wonsik
İnecik, Kemal
Wilson, Laura J.
Kraml, Christina M.
Meredith, Timothy C.
Walker, Suzanne
author_sort Muscato, Jacob D.
collection PubMed
description [Image: see text] Synthetic lethality occurs when inactivation of two genes is lethal but inactivation of either single gene is not. This phenomenon provides an opportunity for efficient compound discovery. Using differential growth screens, one can identify biologically active compounds that selectively inhibit proteins within the synthetic lethal network of any inactivated gene. Here, based purely on synthetic lethalities, we identified two compounds as the only possible inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis from a screen of ∼230,000 compounds. Both compounds proved to inhibit the glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is required for β-lactam resistance in methicillin-resistant S. aureus (MRSA), and the inhibitors restored sensitivity to oxacillin in a highly resistant S. aureus strain. As no other compounds were pursued as possible LTA glycolipid assembly inhibitors, this work demonstrates the extraordinary efficiency of screens that exploit synthetic lethality to discover compounds that target specified pathways. The general approach should be applicable not only to other bacteria but also to eukaryotic cells.
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spelling pubmed-90122252023-02-16 Rapid Inhibitor Discovery by Exploiting Synthetic Lethality Muscato, Jacob D. Morris, Heidi G. Mychack, Aaron Rajagopal, Mithila Baidin, Vadim Hesser, Anthony R. Lee, Wonsik İnecik, Kemal Wilson, Laura J. Kraml, Christina M. Meredith, Timothy C. Walker, Suzanne J Am Chem Soc [Image: see text] Synthetic lethality occurs when inactivation of two genes is lethal but inactivation of either single gene is not. This phenomenon provides an opportunity for efficient compound discovery. Using differential growth screens, one can identify biologically active compounds that selectively inhibit proteins within the synthetic lethal network of any inactivated gene. Here, based purely on synthetic lethalities, we identified two compounds as the only possible inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis from a screen of ∼230,000 compounds. Both compounds proved to inhibit the glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is required for β-lactam resistance in methicillin-resistant S. aureus (MRSA), and the inhibitors restored sensitivity to oxacillin in a highly resistant S. aureus strain. As no other compounds were pursued as possible LTA glycolipid assembly inhibitors, this work demonstrates the extraordinary efficiency of screens that exploit synthetic lethality to discover compounds that target specified pathways. The general approach should be applicable not only to other bacteria but also to eukaryotic cells. American Chemical Society 2022-02-16 2022-03-02 /pmc/articles/PMC9012225/ /pubmed/35170959 http://dx.doi.org/10.1021/jacs.1c12697 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Muscato, Jacob D.
Morris, Heidi G.
Mychack, Aaron
Rajagopal, Mithila
Baidin, Vadim
Hesser, Anthony R.
Lee, Wonsik
İnecik, Kemal
Wilson, Laura J.
Kraml, Christina M.
Meredith, Timothy C.
Walker, Suzanne
Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title_full Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title_fullStr Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title_full_unstemmed Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title_short Rapid Inhibitor Discovery by Exploiting Synthetic Lethality
title_sort rapid inhibitor discovery by exploiting synthetic lethality
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012225/
https://www.ncbi.nlm.nih.gov/pubmed/35170959
http://dx.doi.org/10.1021/jacs.1c12697
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