{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:10:42Z","timestamp":1762506642939,"version":"3.37.3"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"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":[[2015,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Pyrazinamide (PZA) is active against major\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            species (\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            ,\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. africanum<\/jats:named-content>\n            , and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. microti<\/jats:named-content>\n            ) but not against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. bovis<\/jats:named-content>\n            and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. avium<\/jats:named-content>\n            . The latter two are mycobacterial species involved in human and cattle tuberculosis and in HIV coinfections, respectively. PZA is a first-line agent for the treatment of human tuberculosis and requires activation by a mycobacterial pyrazinamidase to form the active metabolite pyrazinoic acid (POA). As a result of this mechanism, resistance to PZA, as is often found in tuberculosis patients, is caused by point mutations in pyrazinamidase. In previous work, we have shown that POA esters and amides synthesized in our laboratory were stable in plasma (M. F. Sim\u00f5es, E. Valente, M. J. G\u00f3mez, E. Anes, and L. Constantino, Eur J Pharm Sci 37:257\u2013263, 2009,\n            <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/dx.doi.org\/10.1016\/j.ejps.2009.02.012\">http:\/\/dx.doi.org\/10.1016\/j.ejps.2009.02.012<\/jats:ext-link>\n            ). Although the amides did not present significant activity, the esters were active against sensitive mycobacteria at concentrations 5- to 10-fold lower than those of PZA. Here, we report that these POA derivatives possess antibacterial efficacy\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>ex vivo<\/jats:italic>\n            against several species and strains of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium<\/jats:named-content>\n            with natural or acquired resistance to PZA, including\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. bovis<\/jats:named-content>\n            and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. avium<\/jats:named-content>\n            . Our results indicate that the resistance probably was overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters have intrinsic activity\n            <jats:italic>per se<\/jats:italic>\n            , we bring evidence here that long-chain fatty alcohols possess a significant antimycobacterial effect against PZA-resistant species and strains and are not mere inactive promoieties. These findings may lead to candidate dual drugs having enhanced activity against both PZA-susceptible and PZA-resistant isolates and being suitable for clinical development.\n          <\/jats:p>","DOI":"10.1128\/aac.00936-15","type":"journal-article","created":{"date-parts":[[2015,10,6]],"date-time":"2015-10-06T02:28:33Z","timestamp":1444098513000},"page":"7693-7699","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria\n            <i>In Vitro<\/i>\n            and\n            <i>Ex Vivo<\/i>\n            within Macrophages"],"prefix":"10.1128","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-1516","authenticated-orcid":false,"given":"David","family":"Pires","sequence":"first","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Em\u00edlia","family":"Valente","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Marta Filipa","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Nuno","family":"Carmo","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Bernard","family":"Testa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Lausanne University Hospital (CHUV), Lausanne, Switzerland"}]},{"given":"Lu\u00eds","family":"Constantino","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-0198","authenticated-orcid":false,"given":"Elsa","family":"Anes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed-ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Global tuberculosis control 2012. WHO publication no. WHO\/HTM\/TB\/2012.6","author":"World Health Organization","year":"2012","unstructured":"World Health Organization. 2012. Global tuberculosis control 2012. WHO publication no. WHO\/HTM\/TB\/2012.6. World Health Organization, Geneva, Switzerland."},{"key":"e_1_3_2_3_2","first-page":"6","article-title":"The curious characteristics of pyrazinamide: a review","volume":"7","author":"Zhang Y","year":"2003","unstructured":"Zhang Y, Mitchison D. 2003. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis 7:6\u201321.","journal-title":"Int J Tuberc Lung Dis"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.7.2044-2049.1999"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-3879(85)90040-6"},{"key":"e_1_3_2_6_2","first-page":"1287","article-title":"Pyrazinamide is not active in vitro against Mycobacterium avium complex","volume":"134","author":"Heifets LB","year":"1986","unstructured":"Heifets LB, Iseman MD, Crowle AJ, Lindholm-Levy PJ. 1986. Pyrazinamide is not active in vitro against Mycobacterium avium complex. Am Rev Respir Dis 134:1287\u20131288.","journal-title":"Am Rev Respir Dis"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0962-8479(92)90044-K"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00085a007"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0696-662"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.540"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.1.362"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/13500872-145-6-1359"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00020a003"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm950538t"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2009.02.012"},{"key":"e_1_3_2_16_2","first-page":"529","article-title":"On the killing of mycobacteria by macrophages","volume":"10","author":"Jordao L","year":"2008","unstructured":"Jordao L, Bleck CK, Mayorga L, Griffiths G, Anes E. 2008. On the killing of mycobacteria by macrophages. Cell Microbiol 10:529\u2013548.","journal-title":"Cell Microbiol"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.7.2736-2738.2004"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1036"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2011.02.003"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2006.10.001"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.16.6.1106-1109.1982"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.21.2.200-204.1985"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1021\/ja01610a021","article-title":"Experimental chemotherapy of tuberculosis. III. Ethyl mercaptan and related compounds in tuberculosis","volume":"77","author":"Kushner S","year":"1955","unstructured":"Kushner S, Bach DH, Jr, Centola FLD, Sanjurjo JL, Williams JH. 1955. Experimental chemotherapy of tuberculosis. III. Ethyl mercaptan and related compounds in tuberculosis. J Am Chem Soc 77:1152\u20131155.","journal-title":"J Am Chem Soc"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.83.5.409"},{"key":"e_1_3_2_25_2","first-page":"257","article-title":"The biochemistry of drug metabolism\u2013an introduction. Part 2","volume":"4","author":"Testa B","year":"2007","unstructured":"Testa B, Kramer SD. 2007. The biochemistry of drug metabolism\u2013an introduction. Part 2. Redox reactions and their enzymes. Chem Biodivers 4:257\u2013405.","journal-title":"Redox reactions and their enzymes. Chem Biodivers"},{"key":"e_1_3_2_26_2","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1002\/cbdv.200790169","article-title":"The biochemistry of drug metabolism\u2013an introduction: part 3. Reactions of hydrolysis and their enzymes","volume":"4","author":"Testa B","year":"2007","unstructured":"Testa B, Kramer SD. 2007. The biochemistry of drug metabolism\u2013an introduction: part 3. Reactions of hydrolysis and their enzymes. Chem Biodivers 4:2031\u20132122.","journal-title":"Chem Biodivers"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.1985.tb00811.x"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.1527"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2003.11.008"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/1574-6968.12043"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(05)03584-1"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00936-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00936-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:57:09Z","timestamp":1645484229000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00936-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12]]},"references-count":30,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2015,12]]}},"alternative-id":["10.1128\/AAC.00936-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.00936-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"type":"print","value":"0066-4804"},{"type":"electronic","value":"1098-6596"}],"subject":[],"published":{"date-parts":[[2015,12]]},"assertion":[{"value":"2015-04-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-09-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-11-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}