{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T11:52:10Z","timestamp":1778932330915,"version":"3.51.4"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T00:00:00Z","timestamp":1488326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Dowdle Family Fund"},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI051622"],"award-info":[{"award-number":["AI051622"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"publisher","award":["5T32AI007620-10"],"award-info":[{"award-number":["5T32AI007620-10"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The efficacy of antimicrobial drugs against\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            , an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. However, inside infected macrophages, bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. Here, we describe how pH-dependent partitioning drives asymmetric antimicrobial drug distribution in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis-<\/jats:named-content>\n            infected macrophages. Specifically, weak bases with moderate activity against\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            (fluoxetine, sertraline, and dibucaine) were shown to accumulate intracellularly due to differential permeability and relative abundance of their ionized and nonionized forms. Nonprotonatable analogs of the test compounds did not show this effect. Neutralization of acidic organelles directly with ammonium chloride or indirectly with bafilomycin A1 partially abrogated the growth restriction of these drugs. Using high-performance liquid chromatography, we quantified the degree of accumulation and reversibility upon acidic compartment neutralization in macrophages and observed that accumulation was greater in infected than in uninfected macrophages. We further demonstrate that the efficacy of a clinically used compound, clofazimine, is augmented by pH-based partitioning in a macrophage infection model. Because the parameters which govern this effect are well understood and are amenable to chemical modification, this knowledge may enable the rational development of more effective antibiotics against tuberculosis.\n          <\/jats:p>","DOI":"10.1128\/aac.01639-16","type":"journal-article","created":{"date-parts":[[2017,1,5]],"date-time":"2017-01-05T02:50:32Z","timestamp":1483584632000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Subcellular Partitioning and Intramacrophage Selectivity of Antimicrobial Compounds against Mycobacterium tuberculosis"],"prefix":"10.1128","volume":"61","author":[{"given":"Michael D.","family":"Schump","sequence":"first","affiliation":[{"name":"Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas M.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Berkeley, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn R.","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, Berkeley, California, USA"},{"name":"Department of Chemistry, University of California, Berkeley, California, USA"},{"name":"Department of Chemistry and Howard Hughes Medical Institute, Stanford University, Stanford, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee W.","family":"Riley","sequence":"additional","affiliation":[{"name":"Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61682-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.282.7.677"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.167.4.603"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60410-2"},{"key":"e_1_3_3_6_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. 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