Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis.
Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds...
Published in: | PLOS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2020
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0008224 https://doaj.org/article/ed36932d78294388be2840c2e73d1b52 |
id |
ftdoajarticles:oai:doaj.org/article:ed36932d78294388be2840c2e73d1b52 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:ed36932d78294388be2840c2e73d1b52 2023-05-15T15:12:47+02:00 Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. Tineke Lauwaet Yukiko Miyamoto Sozaburo Ihara Christine Le Jarosław Kalisiak Keith A Korthals Majid Ghassemian Diane K Smith K Barry Sharpless Valery V Fokin Lars Eckmann 2020-04-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008224 https://doaj.org/article/ed36932d78294388be2840c2e73d1b52 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008224 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008224 https://doaj.org/article/ed36932d78294388be2840c2e73d1b52 PLoS Neglected Tropical Diseases, Vol 14, Iss 4, p e0008224 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008224 2022-12-31T07:46:37Z Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5'-nitroimidazole-sensitive and -resistant cells. The list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5'-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 4 e0008224 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Tineke Lauwaet Yukiko Miyamoto Sozaburo Ihara Christine Le Jarosław Kalisiak Keith A Korthals Majid Ghassemian Diane K Smith K Barry Sharpless Valery V Fokin Lars Eckmann Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5'-nitroimidazole-sensitive and -resistant cells. The list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5'-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites. |
format |
Article in Journal/Newspaper |
author |
Tineke Lauwaet Yukiko Miyamoto Sozaburo Ihara Christine Le Jarosław Kalisiak Keith A Korthals Majid Ghassemian Diane K Smith K Barry Sharpless Valery V Fokin Lars Eckmann |
author_facet |
Tineke Lauwaet Yukiko Miyamoto Sozaburo Ihara Christine Le Jarosław Kalisiak Keith A Korthals Majid Ghassemian Diane K Smith K Barry Sharpless Valery V Fokin Lars Eckmann |
author_sort |
Tineke Lauwaet |
title |
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
title_short |
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
title_full |
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
title_fullStr |
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
title_full_unstemmed |
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
title_sort |
click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008224 https://doaj.org/article/ed36932d78294388be2840c2e73d1b52 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 4, p e0008224 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008224 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008224 https://doaj.org/article/ed36932d78294388be2840c2e73d1b52 |
op_doi |
https://doi.org/10.1371/journal.pntd.0008224 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
4 |
container_start_page |
e0008224 |
_version_ |
1766343419420999680 |