Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.
Identifieur interne : 000024 ( PubMed/Checkpoint ); précédent : 000023; suivant : 000025Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.
Auteurs : Richa Mishra [Inde] ; Sakshi Kohli [Inde] ; Nitish Malhotra [Inde] ; Parijat Bandyopadhyay [Inde] ; Mansi Mehta [Inde] ; Mohamedhusen Munshi [Inde] ; Vasista Adiga [Inde] ; Vijay Kamal Ahuja [Inde] ; Radha K. Shandil [Inde] ; Raju S. Rajmani [Inde] ; Aswin Sai Narain Seshasayee [Inde] ; Amit Singh [Inde]Source :
- Science translational medicine [ 1946-6242 ] ; 2019.
Abstract
The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (Cmax and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.
DOI: 10.1126/scitranslmed.aaw6635
PubMed: 31723039
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560012</wicri:noRegion></affiliation></author><author><name sortKey="Kohli, Sakshi" sort="Kohli, Sakshi" uniqKey="Kohli S" first="Sakshi" last="Kohli">Sakshi Kohli</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Malhotra, Nitish" sort="Malhotra, Nitish" uniqKey="Malhotra N" first="Nitish" last="Malhotra">Nitish Malhotra</name><affiliation wicri:level="1"><nlm:affiliation>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065</wicri:regionArea><wicri:noRegion>Bangalore 560065</wicri:noRegion></affiliation></author><author><name sortKey="Bandyopadhyay, Parijat" sort="Bandyopadhyay, Parijat" uniqKey="Bandyopadhyay P" first="Parijat" last="Bandyopadhyay">Parijat Bandyopadhyay</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Mehta, Mansi" sort="Mehta, Mansi" uniqKey="Mehta M" first="Mansi" last="Mehta">Mansi Mehta</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Munshi, Mohamedhusen" sort="Munshi, Mohamedhusen" uniqKey="Munshi M" first="Mohamedhusen" last="Munshi">Mohamedhusen Munshi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Adiga, Vasista" sort="Adiga, Vasista" uniqKey="Adiga V" first="Vasista" last="Adiga">Vasista Adiga</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Ahuja, Vijay Kamal" sort="Ahuja, Vijay Kamal" uniqKey="Ahuja V" first="Vijay Kamal" last="Ahuja">Vijay Kamal Ahuja</name><affiliation wicri:level="1"><nlm:affiliation>Foundation for Neglected Disease Research, Bangalore 560065, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Foundation for Neglected Disease Research, Bangalore 560065</wicri:regionArea><wicri:noRegion>Bangalore 560065</wicri:noRegion></affiliation></author><author><name sortKey="Shandil, Radha K" sort="Shandil, Radha K" uniqKey="Shandil R" first="Radha K" last="Shandil">Radha K. Shandil</name><affiliation wicri:level="1"><nlm:affiliation>Foundation for Neglected Disease Research, Bangalore 560065, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Foundation for Neglected Disease Research, Bangalore 560065</wicri:regionArea><wicri:noRegion>Bangalore 560065</wicri:noRegion></affiliation></author><author><name sortKey="Rajmani, Raju S" sort="Rajmani, Raju S" uniqKey="Rajmani R" first="Raju S" last="Rajmani">Raju S. Rajmani</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author><author><name sortKey="Seshasayee, Aswin Sai Narain" sort="Seshasayee, Aswin Sai Narain" uniqKey="Seshasayee A" first="Aswin Sai Narain" last="Seshasayee">Aswin Sai Narain Seshasayee</name><affiliation wicri:level="1"><nlm:affiliation>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065</wicri:regionArea><wicri:noRegion>Bangalore 560065</wicri:noRegion></affiliation></author><author><name sortKey="Singh, Amit" sort="Singh, Amit" uniqKey="Singh A" first="Amit" last="Singh">Amit Singh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. asingh@iisc.ac.in.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012</wicri:regionArea><wicri:noRegion>Bangalore 560012</wicri:noRegion></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The capacity of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in <i>Mtb</i> populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of <i>Mtb</i> to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H<sub>2</sub>S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when <i>Mtb</i> infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant <i>Mtb</i>, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (<i>C</i><sub>max</sub> and AUC<sub>last</sub>) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating <i>Mtb</i> and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">31723039</PMID><DateRevised><Year>2020</Year><Month>01</Month><Day>08</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1946-6242</ISSN><JournalIssue CitedMedium="Internet"><Volume>11</Volume><Issue>518</Issue><PubDate><Year>2019</Year><Month>Nov</Month><Day>13</Day></PubDate></JournalIssue><Title>Science translational medicine</Title><ISOAbbreviation>Sci Transl Med</ISOAbbreviation></Journal><ArticleTitle>Targeting redox heterogeneity to counteract drug tolerance in replicating <i>Mycobacterium tuberculosis</i>.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">eaaw6635</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1126/scitranslmed.aaw6635</ELocationID><Abstract><AbstractText>The capacity of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in <i>Mtb</i> populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of <i>Mtb</i> to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H<sub>2</sub>S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when <i>Mtb</i> infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant <i>Mtb</i>, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (<i>C</i><sub>max</sub> and AUC<sub>last</sub>) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating <i>Mtb</i> and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.</AbstractText><CopyrightInformation>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mishra</LastName><ForeName>Richa</ForeName><Initials>R</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-2735-6894</Identifier><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kohli</LastName><ForeName>Sakshi</ForeName><Initials>S</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-1444-584X</Identifier><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Malhotra</LastName><ForeName>Nitish</ForeName><Initials>N</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-8580-9623</Identifier><AffiliationInfo><Affiliation>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bandyopadhyay</LastName><ForeName>Parijat</ForeName><Initials>P</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-9666-7445</Identifier><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mehta</LastName><ForeName>Mansi</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Munshi</LastName><ForeName>MohamedHusen</ForeName><Initials>M</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-2764-5322</Identifier><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adiga</LastName><ForeName>Vasista</ForeName><Initials>V</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-6996-4786</Identifier><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ahuja</LastName><ForeName>Vijay Kamal</ForeName><Initials>VK</Initials><AffiliationInfo><Affiliation>Foundation for Neglected Disease Research, Bangalore 560065, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shandil</LastName><ForeName>Radha K</ForeName><Initials>RK</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-0908-1340</Identifier><AffiliationInfo><Affiliation>Foundation for Neglected Disease Research, Bangalore 560065, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajmani</LastName><ForeName>Raju S</ForeName><Initials>RS</Initials><AffiliationInfo><Affiliation>Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Seshasayee</LastName><ForeName>Aswin Sai Narain</ForeName><Initials>ASN</Initials><AffiliationInfo><Affiliation>National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Amit</ForeName><Initials>A</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-6761-1664</Identifier><AffiliationInfo><Affiliation>Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. asingh@iisc.ac.in.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Sci Transl Med</MedlineTA><NlmUniqueID>101505086</NlmUniqueID><ISSNLinking>1946-6234</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>01</Month><Day>15</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>06</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>10</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>11</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>11</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>11</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31723039</ArticleId><ArticleId IdType="pii">11/518/eaaw6635</ArticleId><ArticleId IdType="doi">10.1126/scitranslmed.aaw6635</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Inde</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Mishra, Richa" sort="Mishra, Richa" uniqKey="Mishra R" first="Richa" last="Mishra">Richa Mishra</name></noRegion><name sortKey="Adiga, Vasista" sort="Adiga, Vasista" uniqKey="Adiga V" first="Vasista" last="Adiga">Vasista Adiga</name><name sortKey="Ahuja, Vijay Kamal" sort="Ahuja, Vijay Kamal" uniqKey="Ahuja V" first="Vijay Kamal" last="Ahuja">Vijay Kamal Ahuja</name><name sortKey="Bandyopadhyay, Parijat" sort="Bandyopadhyay, Parijat" uniqKey="Bandyopadhyay P" first="Parijat" last="Bandyopadhyay">Parijat Bandyopadhyay</name><name sortKey="Kohli, Sakshi" sort="Kohli, Sakshi" uniqKey="Kohli S" first="Sakshi" last="Kohli">Sakshi Kohli</name><name sortKey="Malhotra, Nitish" sort="Malhotra, Nitish" uniqKey="Malhotra N" first="Nitish" last="Malhotra">Nitish Malhotra</name><name sortKey="Mehta, Mansi" sort="Mehta, Mansi" uniqKey="Mehta M" first="Mansi" last="Mehta">Mansi Mehta</name><name sortKey="Munshi, Mohamedhusen" sort="Munshi, Mohamedhusen" uniqKey="Munshi M" first="Mohamedhusen" last="Munshi">Mohamedhusen Munshi</name><name sortKey="Rajmani, Raju S" sort="Rajmani, Raju S" uniqKey="Rajmani R" first="Raju S" last="Rajmani">Raju S. Rajmani</name><name sortKey="Seshasayee, Aswin Sai Narain" sort="Seshasayee, Aswin Sai Narain" uniqKey="Seshasayee A" first="Aswin Sai Narain" last="Seshasayee">Aswin Sai Narain Seshasayee</name><name sortKey="Shandil, Radha K" sort="Shandil, Radha K" uniqKey="Shandil R" first="Radha K" last="Shandil">Radha K. Shandil</name><name sortKey="Singh, Amit" sort="Singh, Amit" uniqKey="Singh A" first="Amit" last="Singh">Amit Singh</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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