A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
Identifieur interne : 001C86 ( PubMed/Corpus ); précédent : 001C85; suivant : 001C87A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
Auteurs : Christian S. Lentz ; Victoria Halls ; Jeffrey S. Hannam ; Björn Niebel ; Uta Strübing ; Günter Mayer ; Achim Hoerauf ; Michael Famulok ; Kenneth M. PfarrSource :
- Chemistry & biology [ 1879-1301 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Antiprotozoal Agents (chemistry), Antiprotozoal Agents (pharmacology), Antiprotozoal Agents (therapeutic use), Benzimidazoles (chemistry), Benzimidazoles (pharmacology), Benzimidazoles (therapeutic use), Drug Design, Elephantiasis, Filarial (drug therapy), Filarioidea (drug effects), Heme (biosynthesis), High-Throughput Screening Assays, Humans, Kinetics, Magnesium (chemistry), Magnesium (metabolism), Porphobilinogen Synthase (antagonists & inhibitors), Porphobilinogen Synthase (metabolism), Symbiosis, Thiophenes (chemistry), Thiophenes (pharmacology), Thiophenes (therapeutic use), Wolbachia (enzymology), Wolbachia (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Porphobilinogen Synthase.
- chemical , biosynthesis : Heme.
- chemical , chemistry : Antiprotozoal Agents, Benzimidazoles, Magnesium, Thiophenes.
- chemical , metabolism : Magnesium, Porphobilinogen Synthase.
- chemical , pharmacology : Antiprotozoal Agents, Benzimidazoles, Thiophenes.
- chemical , therapeutic use : Antiprotozoal Agents, Benzimidazoles, Thiophenes.
- drug effects : Filarioidea.
- drug therapy : Elephantiasis, Filarial.
- enzymology : Wolbachia.
- metabolism : Wolbachia.
- Animals, Drug Design, High-Throughput Screening Assays, Humans, Kinetics, Symbiosis.
Abstract
Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.
DOI: 10.1016/j.chembiol.2012.11.009
PubMed: 23438747
Links to Exploration step
pubmed:23438747Le document en format XML
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Hannam</name></author><author><name sortKey="Niebel, Bjorn" sort="Niebel, Bjorn" uniqKey="Niebel B" first="Björn" last="Niebel">Björn Niebel</name></author><author><name sortKey="Strubing, Uta" sort="Strubing, Uta" uniqKey="Strubing U" first="Uta" last="Strübing">Uta Strübing</name></author><author><name sortKey="Mayer, Gunter" sort="Mayer, Gunter" uniqKey="Mayer G" first="Günter" last="Mayer">Günter Mayer</name></author><author><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name></author><author><name sortKey="Famulok, Michael" sort="Famulok, Michael" uniqKey="Famulok M" first="Michael" last="Famulok">Michael Famulok</name></author><author><name sortKey="Pfarr, Kenneth M" sort="Pfarr, Kenneth M" uniqKey="Pfarr K" first="Kenneth M" last="Pfarr">Kenneth M. 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Lentz</name><affiliation><nlm:affiliation>Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Halls, Victoria" sort="Halls, Victoria" uniqKey="Halls V" first="Victoria" last="Halls">Victoria Halls</name></author><author><name sortKey="Hannam, Jeffrey S" sort="Hannam, Jeffrey S" uniqKey="Hannam J" first="Jeffrey S" last="Hannam">Jeffrey S. Hannam</name></author><author><name sortKey="Niebel, Bjorn" sort="Niebel, Bjorn" uniqKey="Niebel B" first="Björn" last="Niebel">Björn Niebel</name></author><author><name sortKey="Strubing, Uta" sort="Strubing, Uta" uniqKey="Strubing U" first="Uta" last="Strübing">Uta Strübing</name></author><author><name sortKey="Mayer, Gunter" sort="Mayer, Gunter" uniqKey="Mayer G" first="Günter" last="Mayer">Günter Mayer</name></author><author><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name></author><author><name sortKey="Famulok, Michael" sort="Famulok, Michael" uniqKey="Famulok M" first="Michael" last="Famulok">Michael Famulok</name></author><author><name sortKey="Pfarr, Kenneth M" sort="Pfarr, Kenneth M" uniqKey="Pfarr K" first="Kenneth M" last="Pfarr">Kenneth M. Pfarr</name></author></analytic><series><title level="j">Chemistry & biology</title><idno type="eISSN">1879-1301</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiprotozoal Agents (chemistry)</term><term>Antiprotozoal Agents (pharmacology)</term><term>Antiprotozoal Agents (therapeutic use)</term><term>Benzimidazoles (chemistry)</term><term>Benzimidazoles (pharmacology)</term><term>Benzimidazoles (therapeutic use)</term><term>Drug Design</term><term>Elephantiasis, Filarial (drug therapy)</term><term>Filarioidea (drug effects)</term><term>Heme (biosynthesis)</term><term>High-Throughput Screening Assays</term><term>Humans</term><term>Kinetics</term><term>Magnesium (chemistry)</term><term>Magnesium (metabolism)</term><term>Porphobilinogen Synthase (antagonists & inhibitors)</term><term>Porphobilinogen Synthase (metabolism)</term><term>Symbiosis</term><term>Thiophenes (chemistry)</term><term>Thiophenes (pharmacology)</term><term>Thiophenes (therapeutic use)</term><term>Wolbachia (enzymology)</term><term>Wolbachia (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Porphobilinogen Synthase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Heme</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiprotozoal Agents</term><term>Benzimidazoles</term><term>Magnesium</term><term>Thiophenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Magnesium</term><term>Porphobilinogen Synthase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiprotozoal Agents</term><term>Benzimidazoles</term><term>Thiophenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiprotozoal Agents</term><term>Benzimidazoles</term><term>Thiophenes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Filarioidea</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Elephantiasis, Filarial</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Wolbachia</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Wolbachia</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Drug Design</term><term>High-Throughput Screening Assays</term><term>Humans</term><term>Kinetics</term><term>Symbiosis</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23438747</PMID><DateCreated><Year>2013</Year><Month>02</Month><Day>26</Day></DateCreated><DateCompleted><Year>2013</Year><Month>08</Month><Day>30</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1879-1301</ISSN><JournalIssue CitedMedium="Internet"><Volume>20</Volume><Issue>2</Issue><PubDate><Year>2013</Year><Month>Feb</Month><Day>21</Day></PubDate></JournalIssue><Title>Chemistry & biology</Title><ISOAbbreviation>Chem. Biol.</ISOAbbreviation></Journal><ArticleTitle>A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.</ArticleTitle><Pagination><MedlinePgn>177-87</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.chembiol.2012.11.009</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S1074-5521(12)00457-7</ELocationID><Abstract><AbstractText>Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.</AbstractText><CopyrightInformation>Copyright © 2013 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lentz</LastName><ForeName>Christian S</ForeName><Initials>CS</Initials><AffiliationInfo><Affiliation>Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Halls</LastName><ForeName>Victoria</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Hannam</LastName><ForeName>Jeffrey S</ForeName><Initials>JS</Initials></Author><Author ValidYN="Y"><LastName>Niebel</LastName><ForeName>Björn</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Strübing</LastName><ForeName>Uta</ForeName><Initials>U</Initials></Author><Author ValidYN="Y"><LastName>Mayer</LastName><ForeName>Günter</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Hoerauf</LastName><ForeName>Achim</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Famulok</LastName><ForeName>Michael</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Pfarr</LastName><ForeName>Kenneth M</ForeName><Initials>KM</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Chem Biol</MedlineTA><NlmUniqueID>9500160</NlmUniqueID><ISSNLinking>1074-5521</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000981">Antiprotozoal Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001562">Benzimidazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013876">Thiophenes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C583087">wALADin1 compound</NameOfSubstance></Chemical><Chemical><RegistryNumber>42VZT0U6YR</RegistryNumber><NameOfSubstance UI="D006418">Heme</NameOfSubstance></Chemical><Chemical><RegistryNumber>E24GX49LD8</RegistryNumber><NameOfSubstance UI="C031000">benzimidazole</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.2.1.24</RegistryNumber><NameOfSubstance UI="D000623">Porphobilinogen Synthase</NameOfSubstance></Chemical><Chemical><RegistryNumber>I38ZP9992A</RegistryNumber><NameOfSubstance UI="D008274">Magnesium</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000981" MajorTopicYN="N">Antiprotozoal Agents</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001562" MajorTopicYN="N">Benzimidazoles</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="N">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004605" MajorTopicYN="N">Elephantiasis, Filarial</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005370" MajorTopicYN="N">Filarioidea</DescriptorName><QualifierName 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UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013559" MajorTopicYN="N">Symbiosis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013876" MajorTopicYN="N">Thiophenes</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020577" MajorTopicYN="N">Wolbachia</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>09</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2012</Year><Month>11</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>11</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2013</Year><Month>2</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2013</Year><Month>2</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>8</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">23438747</ArticleId><ArticleId IdType="pii">S1074-5521(12)00457-7</ArticleId><ArticleId IdType="doi">10.1016/j.chembiol.2012.11.009</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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