Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility
As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than...
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| Veröffentlicht in: | PloS one 2018-11, Vol.13 (11), p.e0207469-e0207469 |
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| creator | Lee, Bai-Yu Clemens, Daniel L Silva, Aleidy Dillon, Barbara Jane Masleša-Galić, Saša Nava, Susana Ho, Chih-Ming Horwitz, Marcus A |
| description | As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p |
| doi_str_mv | 10.1371/journal.pone.0207469 |
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Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0207469</identifier><identifier>PMID: 30427938</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject><![CDATA[Adamantane - administration & dosage ; Adamantane - analogs & derivatives ; Aerospace engineering ; Animal models ; Animals ; Antitubercular Agents - administration & dosage ; Biology and Life Sciences ; Clofazimine ; Clofazimine - administration & dosage ; Cures ; Diarylquinolines - administration & dosage ; Disease Models, Animal ; Drug Combinations ; Drug dosages ; Drug resistance ; Ethylenediamines - administration & dosage ; Humans ; Infectious diseases ; Lee, Daniel ; Lesions ; Lung - drug effects ; Lung - physiopathology ; Lungs ; Medicine ; Medicine and Health Sciences ; Mice ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - pathogenicity ; Physical Sciences ; Pyrazinamide ; Pyrazinamide - administration & dosage ; Research and Analysis Methods ; Response surface methodology ; Rodents ; Studies ; Tuberculosis ; Tuberculosis - drug therapy ; Tuberculosis - microbiology ; Tuberculosis - physiopathology]]></subject><ispartof>PloS one, 2018-11, Vol.13 (11), p.e0207469-e0207469</ispartof><rights>2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Lee et al 2018 Lee et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-16a147b212c698c3004298b0ea61e68e1e385a435c41bb797cad29162a20be553</citedby><cites>FETCH-LOGICAL-c526t-16a147b212c698c3004298b0ea61e68e1e385a435c41bb797cad29162a20be553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235396/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235396/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30427938$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Neyrolles, Olivier</contributor><creatorcontrib>Lee, Bai-Yu</creatorcontrib><creatorcontrib>Clemens, Daniel L</creatorcontrib><creatorcontrib>Silva, Aleidy</creatorcontrib><creatorcontrib>Dillon, Barbara Jane</creatorcontrib><creatorcontrib>Masleša-Galić, Saša</creatorcontrib><creatorcontrib>Nava, Susana</creatorcontrib><creatorcontrib>Ho, Chih-Ming</creatorcontrib><creatorcontrib>Horwitz, Marcus A</creatorcontrib><title>Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.</description><subject>Adamantane - administration & dosage</subject><subject>Adamantane - analogs & derivatives</subject><subject>Aerospace engineering</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antitubercular Agents - administration & dosage</subject><subject>Biology and Life Sciences</subject><subject>Clofazimine</subject><subject>Clofazimine - administration & dosage</subject><subject>Cures</subject><subject>Diarylquinolines - administration & dosage</subject><subject>Disease Models, Animal</subject><subject>Drug Combinations</subject><subject>Drug dosages</subject><subject>Drug resistance</subject><subject>Ethylenediamines - administration & dosage</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Lee, Daniel</subject><subject>Lesions</subject><subject>Lung - drug effects</subject><subject>Lung - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Bai-Yu</au><au>Clemens, Daniel L</au><au>Silva, Aleidy</au><au>Dillon, Barbara Jane</au><au>Masleša-Galić, Saša</au><au>Nava, Susana</au><au>Ho, Chih-Ming</au><au>Horwitz, Marcus A</au><au>Neyrolles, Olivier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-11-14</date><risdate>2018</risdate><volume>13</volume><issue>11</issue><spage>e0207469</spage><epage>e0207469</epage><pages>e0207469-e0207469</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30427938</pmid><doi>10.1371/journal.pone.0207469</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adamantane - administration & dosage Adamantane - analogs & derivatives Aerospace engineering Animal models Animals Antitubercular Agents - administration & dosage Biology and Life Sciences Clofazimine Clofazimine - administration & dosage Cures Diarylquinolines - administration & dosage Disease Models, Animal Drug Combinations Drug dosages Drug resistance Ethylenediamines - administration & dosage Humans Infectious diseases Lee, Daniel Lesions Lung - drug effects Lung - physiopathology Lungs Medicine Medicine and Health Sciences Mice Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - pathogenicity Physical Sciences Pyrazinamide Pyrazinamide - administration & dosage Research and Analysis Methods Response surface methodology Rodents Studies Tuberculosis Tuberculosis - drug therapy Tuberculosis - microbiology Tuberculosis - physiopathology |
| title | Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility |
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