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Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance
There is an urgent global need for the development of novel therapeutics to combat the rise of various antibiotic‐resistant superbugs. Enzymes of the branched‐chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti‐microbial drug development. Dihydroxy‐acid dehydratase (...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9543379/ https://www.ncbi.nlm.nih.gov/pubmed/35535733 http://dx.doi.org/10.1002/chem.202200927 |
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author | Bayaraa, Tenuun Gaete, Jose Sutiono, Samuel Kurz, Julia Lonhienne, Thierry Harmer, Jeffrey R. Bernhardt, Paul V. Sieber, Volker Guddat, Luke Schenk, Gerhard |
author_facet | Bayaraa, Tenuun Gaete, Jose Sutiono, Samuel Kurz, Julia Lonhienne, Thierry Harmer, Jeffrey R. Bernhardt, Paul V. Sieber, Volker Guddat, Luke Schenk, Gerhard |
author_sort | Bayaraa, Tenuun |
collection | PubMed |
description | There is an urgent global need for the development of novel therapeutics to combat the rise of various antibiotic‐resistant superbugs. Enzymes of the branched‐chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti‐microbial drug development. Dihydroxy‐acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an Fe−S cluster for catalytic activity and has recently also gained attention as a catalyst in cell‐free enzyme cascades. Two types of Fe−S clusters have been identified in DHADs, i.e. [2Fe−2S] and [4Fe−4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ∼19,000‐fold increase with k(cat) as high as ∼6.7 s(−1)). Inductively‐coupled plasma‐optical emission spectroscopy (ICP‐OES) measurements are consistent with the presence of [4Fe−4S] clusters in both enzymes. N‐isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K (i)=7.8 and 51.6 μM, respectively) and CjDHAD (K (i)=32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti‐microbial chemotherapeutics. |
format | Online Article Text |
id | pubmed-9543379 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95433792022-10-14 Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance Bayaraa, Tenuun Gaete, Jose Sutiono, Samuel Kurz, Julia Lonhienne, Thierry Harmer, Jeffrey R. Bernhardt, Paul V. Sieber, Volker Guddat, Luke Schenk, Gerhard Chemistry Research Articles There is an urgent global need for the development of novel therapeutics to combat the rise of various antibiotic‐resistant superbugs. Enzymes of the branched‐chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti‐microbial drug development. Dihydroxy‐acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an Fe−S cluster for catalytic activity and has recently also gained attention as a catalyst in cell‐free enzyme cascades. Two types of Fe−S clusters have been identified in DHADs, i.e. [2Fe−2S] and [4Fe−4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ∼19,000‐fold increase with k(cat) as high as ∼6.7 s(−1)). Inductively‐coupled plasma‐optical emission spectroscopy (ICP‐OES) measurements are consistent with the presence of [4Fe−4S] clusters in both enzymes. N‐isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K (i)=7.8 and 51.6 μM, respectively) and CjDHAD (K (i)=32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti‐microbial chemotherapeutics. John Wiley and Sons Inc. 2022-06-16 2022-08-04 /pmc/articles/PMC9543379/ /pubmed/35535733 http://dx.doi.org/10.1002/chem.202200927 Text en © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Bayaraa, Tenuun Gaete, Jose Sutiono, Samuel Kurz, Julia Lonhienne, Thierry Harmer, Jeffrey R. Bernhardt, Paul V. Sieber, Volker Guddat, Luke Schenk, Gerhard Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title | Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title_full | Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title_fullStr | Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title_full_unstemmed | Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title_short | Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance |
title_sort | dihydroxy‐acid dehydratases from pathogenic bacteria: emerging drug targets to combat antibiotic resistance |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9543379/ https://www.ncbi.nlm.nih.gov/pubmed/35535733 http://dx.doi.org/10.1002/chem.202200927 |
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