Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux
Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations. To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing oflo...
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| Veröffentlicht in: | American journal of respiratory and critical care medicine 2011-07, Vol.184 (2), p.269-276 |
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| creator | LOUW, Gail E WARREN, Robin M VICTOR, Thomas C GEY VAN PITTIUS, Nicolaas C LEON, Rosalba JIMENEZ, Adelina HERNANDEZ-PANDO, Rogelio MCEVOY, Christopher R. E GROBBELAAR, Melanie MURRAY, Megan VAN HELDEN, Paul D |
| description | Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.
To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.
Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.
Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).
Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment. |
| doi_str_mv | 10.1164/rccm.201011-1924OC |
| format | Article |
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To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.
Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.
Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).
Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.201011-1924OC</identifier><identifier>PMID: 21512166</identifier><language>eng</language><publisher>New York, NY: American Thoracic Society</publisher><subject>Adrenergic Uptake Inhibitors - pharmacology ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Anti-Bacterial Agents - pharmacology ; Antibiotics ; Antibiotics, Antitubercular - pharmacology ; Bacterial Proteins - drug effects ; Bacterial Proteins - genetics ; Biological and medical sciences ; Calcium Channel Blockers - pharmacology ; Cell Culture Techniques ; Cell division ; Disease Models, Animal ; DNA-Directed RNA Polymerases ; Drug resistance ; Genes ; Intensive care medicine ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Miscellaneous ; Mutation ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - genetics ; Ofloxacin - pharmacology ; Polymerase chain reaction ; Reserpine - pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Rifampin - pharmacology ; RNA polymerase ; Tuberculosis ; Tuberculosis, Multidrug-Resistant - drug therapy ; Tuberculosis, Multidrug-Resistant - genetics ; Verapamil - pharmacology</subject><ispartof>American journal of respiratory and critical care medicine, 2011-07, Vol.184 (2), p.269-276</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright American Thoracic Society Jul 15, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c458t-8aeadbb5d1d4b95dccb86e92ad7174e34eacffe9bb98becf9fe7b5b0d97757033</citedby><cites>FETCH-LOGICAL-c458t-8aeadbb5d1d4b95dccb86e92ad7174e34eacffe9bb98becf9fe7b5b0d97757033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,4025,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24395714$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21512166$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LOUW, Gail E</creatorcontrib><creatorcontrib>WARREN, Robin M</creatorcontrib><creatorcontrib>VICTOR, Thomas C</creatorcontrib><creatorcontrib>GEY VAN PITTIUS, Nicolaas C</creatorcontrib><creatorcontrib>LEON, Rosalba</creatorcontrib><creatorcontrib>JIMENEZ, Adelina</creatorcontrib><creatorcontrib>HERNANDEZ-PANDO, Rogelio</creatorcontrib><creatorcontrib>MCEVOY, Christopher R. E</creatorcontrib><creatorcontrib>GROBBELAAR, Melanie</creatorcontrib><creatorcontrib>MURRAY, Megan</creatorcontrib><creatorcontrib>VAN HELDEN, Paul D</creatorcontrib><title>Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.
To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.
Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.
Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).
Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.</description><subject>Adrenergic Uptake Inhibitors - pharmacology</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibiotics</subject><subject>Antibiotics, Antitubercular - pharmacology</subject><subject>Bacterial Proteins - drug effects</subject><subject>Bacterial Proteins - genetics</subject><subject>Biological and medical sciences</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Cell Culture Techniques</subject><subject>Cell division</subject><subject>Disease Models, Animal</subject><subject>DNA-Directed RNA Polymerases</subject><subject>Drug resistance</subject><subject>Genes</subject><subject>Intensive care medicine</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microbial Sensitivity Tests</subject><subject>Miscellaneous</subject><subject>Mutation</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Ofloxacin - pharmacology</subject><subject>Polymerase chain reaction</subject><subject>Reserpine - pharmacology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Rifampin - pharmacology</subject><subject>RNA polymerase</subject><subject>Tuberculosis</subject><subject>Tuberculosis, Multidrug-Resistant - drug therapy</subject><subject>Tuberculosis, Multidrug-Resistant - genetics</subject><subject>Verapamil - pharmacology</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkVuLFDEQhYMo7kX_gA_SCOJTr0l30um8CMuwrsLKwKrgW0jSlZ0s3Z02F9n592accbyQhwTqO6eqchB6QfAFIR19G4yZLhpMMCE1EQ1drx6hU8JaVlPB8ePyxrytKRXfTtBZjPcYk6Yn-Ck6aQgjDem6U7TcOqumxRk3V7cwZAOx-pyjgSU57UaXtlXy1dqO_kHtmB12VNQBootJzan6tDVeK5MguDxVKWsIJo--lKu0CT7fbaora8f88Aw9sWqM8Pxwn6Ov76--rD7UN-vrj6vLm9pQ1qe6V6AGrdlABqoFG4zRfQeiUQMnnEJLQRlrQWgteg3GCgtcM40HwTnjuG3P0bu975L1BIOBOQU1yiW4SYWt9MrJfyuz28g7_0O2neg5o8XgzcEg-O8ZYpKTK_8yjmoGn6PseV_aMEEK-eo_8t7nMJftfkGMllOgZg-Z4GMMYI-jECx3ccpdnHIfp9zHWUQv_17iKPmdXwFeHwAVjRptULNx8Q9HW8E4oe1P-P2uuQ</recordid><startdate>20110715</startdate><enddate>20110715</enddate><creator>LOUW, Gail E</creator><creator>WARREN, Robin M</creator><creator>VICTOR, Thomas C</creator><creator>GEY VAN PITTIUS, Nicolaas C</creator><creator>LEON, Rosalba</creator><creator>JIMENEZ, Adelina</creator><creator>HERNANDEZ-PANDO, Rogelio</creator><creator>MCEVOY, Christopher R. E</creator><creator>GROBBELAAR, Melanie</creator><creator>MURRAY, Megan</creator><creator>VAN HELDEN, Paul D</creator><general>American Thoracic Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110715</creationdate><title>Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux</title><author>LOUW, Gail E ; WARREN, Robin M ; VICTOR, Thomas C ; GEY VAN PITTIUS, Nicolaas C ; LEON, Rosalba ; JIMENEZ, Adelina ; HERNANDEZ-PANDO, Rogelio ; MCEVOY, Christopher R. 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Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibiotics</topic><topic>Antibiotics, Antitubercular - pharmacology</topic><topic>Bacterial Proteins - drug effects</topic><topic>Bacterial Proteins - genetics</topic><topic>Biological and medical sciences</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Cell Culture Techniques</topic><topic>Cell division</topic><topic>Disease Models, Animal</topic><topic>DNA-Directed RNA Polymerases</topic><topic>Drug resistance</topic><topic>Genes</topic><topic>Intensive care medicine</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Microbial Sensitivity Tests</topic><topic>Miscellaneous</topic><topic>Mutation</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Ofloxacin - pharmacology</topic><topic>Polymerase chain reaction</topic><topic>Reserpine - pharmacology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Rifampin - pharmacology</topic><topic>RNA polymerase</topic><topic>Tuberculosis</topic><topic>Tuberculosis, Multidrug-Resistant - drug therapy</topic><topic>Tuberculosis, Multidrug-Resistant - genetics</topic><topic>Verapamil - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LOUW, Gail E</creatorcontrib><creatorcontrib>WARREN, Robin M</creatorcontrib><creatorcontrib>VICTOR, Thomas C</creatorcontrib><creatorcontrib>GEY VAN PITTIUS, Nicolaas C</creatorcontrib><creatorcontrib>LEON, Rosalba</creatorcontrib><creatorcontrib>JIMENEZ, Adelina</creatorcontrib><creatorcontrib>HERNANDEZ-PANDO, Rogelio</creatorcontrib><creatorcontrib>MCEVOY, Christopher R. 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E</au><au>GROBBELAAR, Melanie</au><au>MURRAY, Megan</au><au>VAN HELDEN, Paul D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2011-07-15</date><risdate>2011</risdate><volume>184</volume><issue>2</issue><spage>269</spage><epage>276</epage><pages>269-276</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.
To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.
Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.
Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).
Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.</abstract><cop>New York, NY</cop><pub>American Thoracic Society</pub><pmid>21512166</pmid><doi>10.1164/rccm.201011-1924OC</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | American journal of respiratory and critical care medicine, 2011-07, Vol.184 (2), p.269-276 |
| issn | 1073-449X 1535-4970 |
| language | eng |
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| source | MEDLINE; Journals@Ovid Complete; American Thoracic Society (ATS) Journals Online; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adrenergic Uptake Inhibitors - pharmacology Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Anti-Bacterial Agents - pharmacology Antibiotics Antibiotics, Antitubercular - pharmacology Bacterial Proteins - drug effects Bacterial Proteins - genetics Biological and medical sciences Calcium Channel Blockers - pharmacology Cell Culture Techniques Cell division Disease Models, Animal DNA-Directed RNA Polymerases Drug resistance Genes Intensive care medicine Medical sciences Mice Mice, Inbred BALB C Microbial Sensitivity Tests Miscellaneous Mutation Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - genetics Ofloxacin - pharmacology Polymerase chain reaction Reserpine - pharmacology Reverse Transcriptase Polymerase Chain Reaction Rifampin - pharmacology RNA polymerase Tuberculosis Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Multidrug-Resistant - genetics Verapamil - pharmacology |
| title | Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux |
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