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Large-Scale Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination Chemotherapy in Mycobacteria
[Image: see text] The efficacies of all antibiotics against tuberculosis are eventually eroded by resistance. New strategies to discover drugs or drug combinations with higher barriers to resistance are needed. Previously, we reported the application of a large-scale chemical-genetic interaction scr...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958538/ https://www.ncbi.nlm.nih.gov/pubmed/31721551 http://dx.doi.org/10.1021/acsinfecdis.9b00373 |
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author | Johnson, Eachan O. Office, Emma Kawate, Tomohiko Orzechowski, Marek Hung, Deborah T. |
author_facet | Johnson, Eachan O. Office, Emma Kawate, Tomohiko Orzechowski, Marek Hung, Deborah T. |
author_sort | Johnson, Eachan O. |
collection | PubMed |
description | [Image: see text] The efficacies of all antibiotics against tuberculosis are eventually eroded by resistance. New strategies to discover drugs or drug combinations with higher barriers to resistance are needed. Previously, we reported the application of a large-scale chemical-genetic interaction screening strategy called PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) for the discovery of new Mycobacterium tuberculosis inhibitors, which resulted in the identification of the small molecule BRD-8000, an inhibitor of a novel target, EfpA [Johnson et al. (2019) Nature517, 72]. Leveraging the chemical genetic interaction profile of BRD-8000, we identified BRD-9327, another structurally distinct small molecule EfpA inhibitor. We show that the two compounds are synergistic and display collateral sensitivity because of their distinct modes of action and resistance mechanisms. High-level resistance to one increases the sensitivity to and reduces the emergence of resistance to the other. Thus, the combination of BRD-9327 and BRD-8000 represents a proof-of-concept for the novel strategy of leveraging chemical genetics in the design of antimicrobial combination chemotherapy in which mutual collateral sensitivity is exploited. |
format | Online Article Text |
id | pubmed-6958538 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-69585382020-01-15 Large-Scale Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination Chemotherapy in Mycobacteria Johnson, Eachan O. Office, Emma Kawate, Tomohiko Orzechowski, Marek Hung, Deborah T. ACS Infect Dis [Image: see text] The efficacies of all antibiotics against tuberculosis are eventually eroded by resistance. New strategies to discover drugs or drug combinations with higher barriers to resistance are needed. Previously, we reported the application of a large-scale chemical-genetic interaction screening strategy called PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) for the discovery of new Mycobacterium tuberculosis inhibitors, which resulted in the identification of the small molecule BRD-8000, an inhibitor of a novel target, EfpA [Johnson et al. (2019) Nature517, 72]. Leveraging the chemical genetic interaction profile of BRD-8000, we identified BRD-9327, another structurally distinct small molecule EfpA inhibitor. We show that the two compounds are synergistic and display collateral sensitivity because of their distinct modes of action and resistance mechanisms. High-level resistance to one increases the sensitivity to and reduces the emergence of resistance to the other. Thus, the combination of BRD-9327 and BRD-8000 represents a proof-of-concept for the novel strategy of leveraging chemical genetics in the design of antimicrobial combination chemotherapy in which mutual collateral sensitivity is exploited. American Chemical Society 2019-11-13 2020-01-10 /pmc/articles/PMC6958538/ /pubmed/31721551 http://dx.doi.org/10.1021/acsinfecdis.9b00373 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Johnson, Eachan O. Office, Emma Kawate, Tomohiko Orzechowski, Marek Hung, Deborah T. Large-Scale Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination Chemotherapy in Mycobacteria |
title | Large-Scale
Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination
Chemotherapy in Mycobacteria |
title_full | Large-Scale
Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination
Chemotherapy in Mycobacteria |
title_fullStr | Large-Scale
Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination
Chemotherapy in Mycobacteria |
title_full_unstemmed | Large-Scale
Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination
Chemotherapy in Mycobacteria |
title_short | Large-Scale
Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination
Chemotherapy in Mycobacteria |
title_sort | large-scale
chemical-genetic strategy enables the design of antimicrobial combination
chemotherapy in mycobacteria |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958538/ https://www.ncbi.nlm.nih.gov/pubmed/31721551 http://dx.doi.org/10.1021/acsinfecdis.9b00373 |
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