{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T19:50:21Z","timestamp":1772826621551,"version":"3.50.1"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"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":[[2015,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Drug resistance is a major problem in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            control, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-\n            <jats:italic>a<\/jats:italic>\n            ]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            . In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independent\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            mutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations in\n            <jats:italic>Rv2887<\/jats:italic>\n            were common to all three MP-III-71-resistant mutants, and we confirmed the role of\n            <jats:italic>Rv2887<\/jats:italic>\n            as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>\n            to negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation of\n            <jats:italic>Rv2887<\/jats:italic>\n            abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations of\n            <jats:italic>Rv2887<\/jats:italic>\n            , encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            <jats:italic>Rv2887<\/jats:italic>\n            mutants may involve efflux pump upregulation and also drug methylation.\n          <\/jats:p>","DOI":"10.1128\/aac.01341-15","type":"journal-article","created":{"date-parts":[[2015,8,25]],"date-time":"2015-08-25T01:40:12Z","timestamp":1440466812000},"page":"6873-6881","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Mutation of\n            <i>Rv2887<\/i>\n            , a\n            <i>marR<\/i>\n            -Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent"],"prefix":"10.1128","volume":"59","author":[{"given":"Kathryn","family":"Winglee","sequence":"first","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shichun","family":"Lun","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Pieroni","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, P4T group, University of Parma, Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Kozikowski","sequence":"additional","affiliation":[{"name":"Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Bishai","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Tuberculosis","author":"World Health Organization","year":"2014","unstructured":"World Health Organization. 2014. 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