Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage
Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage,...
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| Veröffentlicht in: | Antimicrobial agents and chemotherapy 2022-07, Vol.66 (7), p.e0032222 |
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| creator | Rivière, Emmanuel Verboven, Lennert Dippenaar, Anzaan Goossens, Sander De Vos, Elise Streicher, Elizabeth Cuypers, Bart Laukens, Kris Ben-Rached, Fathia Rodwell, Timothy C Pain, Arnab Warren, Robin M Heupink, Tim H Van Rie, Annelies |
| description | Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole-genome sequencing to identify variants in bedaquiline-resistance genes in isolates from 509 bedaquiline treatment naive South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline MIC was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the
(
) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher's exact test,
= 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few ( |
| doi_str_mv | 10.1128/aac.00322-22 |
| format | Article |
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(
) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher's exact test,
= 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline-resistance acquisition and treatment outcome.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/aac.00322-22</identifier><identifier>PMID: 35758754</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Antitubercular Agents - pharmacology ; Antitubercular Agents - therapeutic use ; Diarylquinolines - pharmacology ; Epidemiology and Surveillance ; Humans ; Microbial Genetics ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis - genetics ; Phylogeny ; Prevalence ; Tuberculosis, Multidrug-Resistant - drug therapy ; Tuberculosis, Multidrug-Resistant - epidemiology ; Tuberculosis, Multidrug-Resistant - microbiology</subject><ispartof>Antimicrobial agents and chemotherapy, 2022-07, Vol.66 (7), p.e0032222</ispartof><rights>Copyright © 2022 American Society for Microbiology.</rights><rights>Copyright © 2022 American Society for Microbiology. 2022 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a418t-2d08b15c335bf6d288e52c97bfe4c81221d3b8d3f2d693b6f4c01c06a5303a803</citedby><cites>FETCH-LOGICAL-a418t-2d08b15c335bf6d288e52c97bfe4c81221d3b8d3f2d693b6f4c01c06a5303a803</cites><orcidid>0000-0002-3406-4219 ; 0000-0002-7198-1470 ; 0000-0002-2511-7534 ; 0000-0003-3410-218X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295546/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295546/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35758754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rivière, Emmanuel</creatorcontrib><creatorcontrib>Verboven, Lennert</creatorcontrib><creatorcontrib>Dippenaar, Anzaan</creatorcontrib><creatorcontrib>Goossens, Sander</creatorcontrib><creatorcontrib>De Vos, Elise</creatorcontrib><creatorcontrib>Streicher, Elizabeth</creatorcontrib><creatorcontrib>Cuypers, Bart</creatorcontrib><creatorcontrib>Laukens, Kris</creatorcontrib><creatorcontrib>Ben-Rached, Fathia</creatorcontrib><creatorcontrib>Rodwell, Timothy C</creatorcontrib><creatorcontrib>Pain, Arnab</creatorcontrib><creatorcontrib>Warren, Robin M</creatorcontrib><creatorcontrib>Heupink, Tim H</creatorcontrib><creatorcontrib>Van Rie, Annelies</creatorcontrib><title>Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole-genome sequencing to identify variants in bedaquiline-resistance genes in isolates from 509 bedaquiline treatment naive South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline MIC was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the
(
) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher's exact test,
= 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline-resistance acquisition and treatment outcome.</description><subject>Antitubercular Agents - pharmacology</subject><subject>Antitubercular Agents - therapeutic use</subject><subject>Diarylquinolines - pharmacology</subject><subject>Epidemiology and Surveillance</subject><subject>Humans</subject><subject>Microbial Genetics</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Phylogeny</subject><subject>Prevalence</subject><subject>Tuberculosis, Multidrug-Resistant - drug therapy</subject><subject>Tuberculosis, Multidrug-Resistant - epidemiology</subject><subject>Tuberculosis, Multidrug-Resistant - microbiology</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kd9PFDEQxxujkQN989n01eQW-2O71_XBBC8IJIcSo742s-0slOx1oe2e4f_hD7V4QNDEp8nMfOczM_kS8oazfc6Ffg9g9xmTQlRCPCMzzlpdNaptnpMZY01T1ZrVO2Q3pUtWctWyl2RHqoXSC1XPyO1PiB5CTtQH-gkdXE9-8AGrJQTnHWSsvmHyKUOwSI8wYPpAzyJuYMC7yj9TX8BvkJ5B9liYc3rY92gzHQM9PVnOaWHSg5RG64uiFH_5fEFPb-zYgc0Y_bSmeeow2mkYy1K6Kkw4x1fkRQ9Dwtf3cY_8-Hz4fXlcrb4enSwPVhXUXOdKOKY7rqyUqusbJ7RGJWy76HqsreZCcCc77WQvXNPKrulry7hlDSjJJGgm98jHLfdq6tbobPkhwmCuol9DvDEjePN3J_gLcz5uTCtapeqmAOZbgI1jShH7x1nOzJ1bprhl_rhlhCjyd1s5pLUwl-MUQ3nvf9q3T297BD9YKX8DP6yhUA</recordid><startdate>20220719</startdate><enddate>20220719</enddate><creator>Rivière, Emmanuel</creator><creator>Verboven, Lennert</creator><creator>Dippenaar, Anzaan</creator><creator>Goossens, Sander</creator><creator>De Vos, Elise</creator><creator>Streicher, Elizabeth</creator><creator>Cuypers, Bart</creator><creator>Laukens, Kris</creator><creator>Ben-Rached, Fathia</creator><creator>Rodwell, Timothy C</creator><creator>Pain, Arnab</creator><creator>Warren, Robin M</creator><creator>Heupink, Tim H</creator><creator>Van Rie, Annelies</creator><general>American Society for Microbiology</general><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>5PM</scope><orcidid>https://orcid.org/0000-0002-3406-4219</orcidid><orcidid>https://orcid.org/0000-0002-7198-1470</orcidid><orcidid>https://orcid.org/0000-0002-2511-7534</orcidid><orcidid>https://orcid.org/0000-0003-3410-218X</orcidid></search><sort><creationdate>20220719</creationdate><title>Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage</title><author>Rivière, Emmanuel ; Verboven, Lennert ; Dippenaar, Anzaan ; Goossens, Sander ; De Vos, Elise ; Streicher, Elizabeth ; Cuypers, Bart ; Laukens, Kris ; Ben-Rached, Fathia ; Rodwell, Timothy C ; Pain, Arnab ; Warren, Robin M ; Heupink, Tim H ; Van Rie, Annelies</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a418t-2d08b15c335bf6d288e52c97bfe4c81221d3b8d3f2d693b6f4c01c06a5303a803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antitubercular Agents - pharmacology</topic><topic>Antitubercular Agents - therapeutic use</topic><topic>Diarylquinolines - pharmacology</topic><topic>Epidemiology and Surveillance</topic><topic>Humans</topic><topic>Microbial Genetics</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Phylogeny</topic><topic>Prevalence</topic><topic>Tuberculosis, Multidrug-Resistant - drug therapy</topic><topic>Tuberculosis, Multidrug-Resistant - epidemiology</topic><topic>Tuberculosis, Multidrug-Resistant - microbiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rivière, Emmanuel</creatorcontrib><creatorcontrib>Verboven, Lennert</creatorcontrib><creatorcontrib>Dippenaar, Anzaan</creatorcontrib><creatorcontrib>Goossens, Sander</creatorcontrib><creatorcontrib>De Vos, Elise</creatorcontrib><creatorcontrib>Streicher, Elizabeth</creatorcontrib><creatorcontrib>Cuypers, Bart</creatorcontrib><creatorcontrib>Laukens, Kris</creatorcontrib><creatorcontrib>Ben-Rached, Fathia</creatorcontrib><creatorcontrib>Rodwell, Timothy C</creatorcontrib><creatorcontrib>Pain, Arnab</creatorcontrib><creatorcontrib>Warren, Robin M</creatorcontrib><creatorcontrib>Heupink, Tim H</creatorcontrib><creatorcontrib>Van Rie, Annelies</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rivière, Emmanuel</au><au>Verboven, Lennert</au><au>Dippenaar, Anzaan</au><au>Goossens, Sander</au><au>De Vos, Elise</au><au>Streicher, Elizabeth</au><au>Cuypers, Bart</au><au>Laukens, Kris</au><au>Ben-Rached, Fathia</au><au>Rodwell, Timothy C</au><au>Pain, Arnab</au><au>Warren, Robin M</au><au>Heupink, Tim H</au><au>Van Rie, Annelies</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2022-07-19</date><risdate>2022</risdate><volume>66</volume><issue>7</issue><spage>e0032222</spage><pages>e0032222-</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole-genome sequencing to identify variants in bedaquiline-resistance genes in isolates from 509 bedaquiline treatment naive South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline MIC was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the
(
) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher's exact test,
= 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline-resistance acquisition and treatment outcome.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>35758754</pmid><doi>10.1128/aac.00322-22</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-3406-4219</orcidid><orcidid>https://orcid.org/0000-0002-7198-1470</orcidid><orcidid>https://orcid.org/0000-0002-2511-7534</orcidid><orcidid>https://orcid.org/0000-0003-3410-218X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Antitubercular Agents - pharmacology Antitubercular Agents - therapeutic use Diarylquinolines - pharmacology Epidemiology and Surveillance Humans Microbial Genetics Microbial Sensitivity Tests Mycobacterium tuberculosis - genetics Phylogeny Prevalence Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Multidrug-Resistant - epidemiology Tuberculosis, Multidrug-Resistant - microbiology |
| title | Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage |
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