Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.
Identifieur interne : 000200 ( Main/Exploration ); précédent : 000199; suivant : 000201Targeting 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.
Descripteurs français
- KwdFr :
- Acides (MeSH), Animaux (MeSH), Antituberculeux (pharmacologie), Antituberculeux (usage thérapeutique), Chloroquine (pharmacologie), Chloroquine (usage thérapeutique), Cystéine (métabolisme), Femelle (MeSH), Infections à VIH (microbiologie), Interactions médicamenteuses (MeSH), Macrophages (anatomopathologie), Macrophages (effets des médicaments et des substances chimiques), Macrophages (microbiologie), Multirésistance bactérienne aux médicaments (effets des médicaments et des substances chimiques), Mycobacterium tuberculosis (croissance et développement), Mycobacterium tuberculosis (effets des médicaments et des substances chimiques), Mycobacterium tuberculosis (génétique), Oxydoréduction (MeSH), Phagosomes (effets des médicaments et des substances chimiques), Phagosomes (microbiologie), Protéines bactériennes (métabolisme), Récidive (MeSH), Résistance bactérienne aux médicaments (effets des médicaments et des substances chimiques), Souris de lignée BALB C (MeSH), Transcriptome (effets des médicaments et des substances chimiques), Transcriptome (génétique), Tuberculose (microbiologie), Tuberculose (traitement médicamenteux).
- MESH :
- anatomopathologie : Macrophages.
- croissance et développement : Mycobacterium tuberculosis.
- effets des médicaments et des substances chimiques : Macrophages, Multirésistance bactérienne aux médicaments, Mycobacterium tuberculosis, Phagosomes, Résistance bactérienne aux médicaments, Transcriptome.
- génétique : Mycobacterium tuberculosis, Transcriptome.
- microbiologie : Infections à VIH, Macrophages, Phagosomes, Tuberculose.
- métabolisme : Cystéine, Protéines bactériennes.
- pharmacologie : Antituberculeux, Chloroquine.
- traitement médicamenteux : Tuberculose.
- usage thérapeutique : Antituberculeux, Chloroquine.
- Acides, Animaux, Femelle, Interactions médicamenteuses, Oxydoréduction, Récidive, Souris de lignée BALB C.
English descriptors
- KwdEn :
- Acids (MeSH), Animals (MeSH), Antitubercular Agents (pharmacology), Antitubercular Agents (therapeutic use), Bacterial Proteins (metabolism), Chloroquine (pharmacology), Chloroquine (therapeutic use), Cysteine (metabolism), Drug Interactions (MeSH), Drug Resistance, Bacterial (drug effects), Drug Resistance, Multiple, Bacterial (drug effects), Female (MeSH), HIV Infections (microbiology), Macrophages (drug effects), Macrophages (microbiology), Macrophages (pathology), Mice, Inbred BALB C (MeSH), Mycobacterium tuberculosis (drug effects), Mycobacterium tuberculosis (genetics), Mycobacterium tuberculosis (growth & development), Oxidation-Reduction (MeSH), Phagosomes (drug effects), Phagosomes (microbiology), RNA-Seq (MeSH), Recurrence (MeSH), Transcriptome (drug effects), Transcriptome (genetics), Tuberculosis (drug therapy), Tuberculosis (microbiology).
- MESH :
- chemical , metabolism : Bacterial Proteins, Cysteine.
- chemical , pharmacology : Antitubercular Agents, Chloroquine.
- chemical , therapeutic use : Antitubercular Agents, Chloroquine.
- chemical : Acids.
- drug effects : Drug Resistance, Bacterial, Drug Resistance, Multiple, Bacterial, Macrophages, Mycobacterium tuberculosis, Phagosomes, Transcriptome.
- drug therapy : Tuberculosis.
- genetics : Mycobacterium tuberculosis, Transcriptome.
- growth & development : Mycobacterium tuberculosis.
- microbiology : HIV Infections, Macrophages, Phagosomes, Tuberculosis.
- pathology : Macrophages.
- Animals, Drug Interactions, Female, Mice, Inbred BALB C, Oxidation-Reduction, RNA-Seq, Recurrence.
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
PubMed Central: PMC7212044
Affiliations:
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Le document en format XML
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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></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31723039</idno><idno type="pmid">31723039</idno><idno type="doi">10.1126/scitranslmed.aaw6635</idno><idno type="pmc">PMC7212044</idno><idno type="wicri:Area/Main/Corpus">000198</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000198</idno><idno 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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="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><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="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><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="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><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="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><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="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><keywords scheme="KwdEn" xml:lang="en"><term>Acids (MeSH)</term><term>Animals (MeSH)</term><term>Antitubercular Agents (pharmacology)</term><term>Antitubercular Agents (therapeutic use)</term><term>Bacterial Proteins (metabolism)</term><term>Chloroquine (pharmacology)</term><term>Chloroquine (therapeutic use)</term><term>Cysteine (metabolism)</term><term>Drug Interactions (MeSH)</term><term>Drug Resistance, Bacterial (drug effects)</term><term>Drug Resistance, Multiple, Bacterial (drug effects)</term><term>Female (MeSH)</term><term>HIV Infections (microbiology)</term><term>Macrophages (drug effects)</term><term>Macrophages (microbiology)</term><term>Macrophages (pathology)</term><term>Mice, Inbred BALB C (MeSH)</term><term>Mycobacterium tuberculosis (drug effects)</term><term>Mycobacterium tuberculosis (genetics)</term><term>Mycobacterium tuberculosis (growth & development)</term><term>Oxidation-Reduction (MeSH)</term><term>Phagosomes (drug effects)</term><term>Phagosomes (microbiology)</term><term>RNA-Seq (MeSH)</term><term>Recurrence (MeSH)</term><term>Transcriptome (drug effects)</term><term>Transcriptome (genetics)</term><term>Tuberculosis (drug therapy)</term><term>Tuberculosis (microbiology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acides (MeSH)</term><term>Animaux (MeSH)</term><term>Antituberculeux (pharmacologie)</term><term>Antituberculeux (usage thérapeutique)</term><term>Chloroquine (pharmacologie)</term><term>Chloroquine (usage thérapeutique)</term><term>Cystéine (métabolisme)</term><term>Femelle (MeSH)</term><term>Infections à VIH (microbiologie)</term><term>Interactions médicamenteuses (MeSH)</term><term>Macrophages (anatomopathologie)</term><term>Macrophages (effets des médicaments et des substances chimiques)</term><term>Macrophages (microbiologie)</term><term>Multirésistance bactérienne aux médicaments (effets des médicaments et des substances chimiques)</term><term>Mycobacterium tuberculosis (croissance et développement)</term><term>Mycobacterium tuberculosis (effets des médicaments et des substances chimiques)</term><term>Mycobacterium tuberculosis (génétique)</term><term>Oxydoréduction (MeSH)</term><term>Phagosomes (effets des médicaments et des substances chimiques)</term><term>Phagosomes (microbiologie)</term><term>Protéines bactériennes (métabolisme)</term><term>Récidive (MeSH)</term><term>Résistance bactérienne aux médicaments (effets des médicaments et des substances chimiques)</term><term>Souris de lignée BALB C (MeSH)</term><term>Transcriptome (effets des médicaments et des substances chimiques)</term><term>Transcriptome (génétique)</term><term>Tuberculose (microbiologie)</term><term>Tuberculose (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Bacterial Proteins</term><term>Cysteine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antitubercular Agents</term><term>Chloroquine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antitubercular Agents</term><term>Chloroquine</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Acids</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance, Bacterial</term><term>Drug Resistance, Multiple, Bacterial</term><term>Macrophages</term><term>Mycobacterium tuberculosis</term><term>Phagosomes</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Tuberculosis</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Macrophages</term><term>Multirésistance bactérienne aux médicaments</term><term>Mycobacterium tuberculosis</term><term>Phagosomes</term><term>Résistance bactérienne aux médicaments</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mycobacterium tuberculosis</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mycobacterium tuberculosis</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="microbiologie" xml:lang="fr"><term>Infections à VIH</term><term>Macrophages</term><term>Phagosomes</term><term>Tuberculose</term></keywords><keywords scheme="MESH" qualifier="microbiology" xml:lang="en"><term>HIV Infections</term><term>Macrophages</term><term>Phagosomes</term><term>Tuberculosis</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cystéine</term><term>Protéines bactériennes</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antituberculeux</term><term>Chloroquine</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tuberculose</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antituberculeux</term><term>Chloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Drug Interactions</term><term>Female</term><term>Mice, Inbred BALB C</term><term>Oxidation-Reduction</term><term>RNA-Seq</term><term>Recurrence</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acides</term><term>Animaux</term><term>Femelle</term><term>Interactions médicamenteuses</term><term>Oxydoréduction</term><term>Récidive</term><term>Souris de lignée BALB C</term></keywords></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="MEDLINE" Owner="NLM"><PMID Version="1">31723039</PMID><DateCompleted><Year>2020</Year><Month>09</Month><Day>04</Day></DateCompleted><DateRevised><Year>2020</Year><Month>09</Month><Day>11</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>11</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">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">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">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">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">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">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">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">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><GrantList CompleteYN="Y"><Grant><Acronym>WT_</Acronym><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>IA/S/16/2/502700</GrantID><Agency>DBT-Wellcome Trust India Alliance</Agency><Country>India</Country></Grant></GrantList><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>Sci Transl Med</MedlineTA><NlmUniqueID>101505086</NlmUniqueID><ISSNLinking>1946-6234</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000143">Acids</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000995">Antitubercular Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001426">Bacterial Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>K848JZ4886</RegistryNumber><NameOfSubstance UI="D003545">Cysteine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000143" MajorTopicYN="N">Acids</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000995" MajorTopicYN="N">Antitubercular Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001426" MajorTopicYN="N">Bacterial Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003545" MajorTopicYN="N">Cysteine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004347" MajorTopicYN="N">Drug Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D024881" MajorTopicYN="Y">Drug Resistance, Bacterial</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D024901" MajorTopicYN="N">Drug Resistance, Multiple, Bacterial</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015658" MajorTopicYN="N">HIV Infections</DescriptorName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008264" MajorTopicYN="N">Macrophages</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009169" MajorTopicYN="N">Mycobacterium tuberculosis</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000254" MajorTopicYN="Y">growth & development</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010084" MajorTopicYN="N">Oxidation-Reduction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010588" MajorTopicYN="N">Phagosomes</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000081246" MajorTopicYN="N">RNA-Seq</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012008" MajorTopicYN="N">Recurrence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059467" MajorTopicYN="N">Transcriptome</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014376" MajorTopicYN="N">Tuberculosis</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName></MeshHeading></MeshHeadingList></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>2020</Year><Month>9</Month><Day>5</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><ArticleId IdType="pmc">PMC7212044</ArticleId><ArticleId IdType="mid">EMS86154</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>PLoS One. 2015 Feb 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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="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="Mehta, Mansi" sort="Mehta, Mansi" uniqKey="Mehta M" first="Mansi" last="Mehta">Mansi Mehta</name><name sortKey="Mishra, Richa" sort="Mishra, Richa" uniqKey="Mishra R" first="Richa" last="Mishra">Richa Mishra</name><name sortKey="Munshi, Mohamedhusen" sort="Munshi, Mohamedhusen" uniqKey="Munshi M" first="Mohamedhusen" last="Munshi">Mohamedhusen Munshi</name><name sortKey="Munshi, Mohamedhusen" sort="Munshi, Mohamedhusen" uniqKey="Munshi M" 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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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