{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:33:12Z","timestamp":1790800392626,"version":"4.1.0"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T00:00:00Z","timestamp":1501545600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the\n            <jats:italic>pncA<\/jats:italic>\n            gene. Although resistance to PZA is mostly caused by\n            <jats:italic>pncA<\/jats:italic>\n            mutations and less commonly by\n            <jats:italic>rpsA<\/jats:italic>\n            ,\n            <jats:italic>panD<\/jats:italic>\n            , and\n            <jats:italic>clpC1<\/jats:italic>\n            mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA\/POA efflux and cause PZA resistance in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            . Future studies are needed to assess their roles in PZA resistance in clinical strains.\n          <\/jats:p>","DOI":"10.1128\/aac.00940-17","type":"journal-article","created":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T00:30:26Z","timestamp":1496709026000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis"],"prefix":"10.1128","volume":"61","author":[{"given":"Yumeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"name":"Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Department of infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"WHO\/HTM\/TB\/201613","author":"WHO","year":"2016","unstructured":"WHO. 2016. World Health Organization Report on Global Tuberculosis 2016. Reference no. WHO\/HTM\/TB\/201613. World Health Organization, Geneva, Switzerland."},{"key":"e_1_3_3_3_2","first-page":"6","article-title":"The curious characteristics of pyrazinamide: a review","volume":"7","author":"Zhang Y","year":"2003","unstructured":"Zhang Y MitchisonD. 2003. The curious characteristics of pyrazinamide: a review. 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Expression of genes in mycobacteria. 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