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This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent <jats:italic>Mtb<\/jats:italic> lacking a typical cell wall, and (c) why isoniazid treatment time is remarkably long in contrast to most other antibiotics. To address these questions, a novel comprehensive mode of action of isoniazid has been proposed here. Briefly, isoniazid eradicates latent tuberculosis (TB) by prompting slow differentiation of pro\u2010inflammatory monocytes and providing protection against reactive species\u2010induced \u201cself\u2010necrosis\u201d of phagocytes. In the case of active TB, different immune cells form INH\u2010NAD<jats:sup>+<\/jats:sup> adducts to inhibit <jats:italic>Mtb<\/jats:italic>'s cell wall biosynthesis. This additionally suggests that the antibacterial properties of INH do not rely on KatG of <jats:italic>Mtb<\/jats:italic>. As such, isoniazid\u2010resistant TB needs to be re\u2010evaluated.<\/jats:p>","DOI":"10.1111\/bph.14867","type":"journal-article","created":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T15:03:27Z","timestamp":1568387007000},"page":"4599-4608","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action"],"prefix":"10.1111","volume":"176","author":[{"given":"Saifur R.","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Toronto  Toronto Canada"},{"name":"Advanced Diagnostics, Metabolism, Toronto General Research Institute  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Manialawy","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Toronto  Toronto Canada"},{"name":"Advanced Diagnostics, Metabolism, Toronto General Research Institute  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno G.","family":"Siraki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1281"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13877"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01691-09"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.01.004"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.03.019"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0962-8479(94)90002-7"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2008.07.002"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2011.3"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3109\/02656736.2014.971446"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09247"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13591"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000348676"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2011.04.002"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.6.3707"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.09.003"},{"key":"e_1_2_11_17_1","first-page":"411","article-title":"The granuloma in tuberculosis: Dynamics of a host\u2013pathogen collusion","volume":"3","author":"Ehlers S.","year":"2012","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01335.x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.4.1277-1281.1998"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.3.1744-1753.2005"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.6.3300"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.09.030"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2011.14"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0098-2997(01)00010-3"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/14.12.2857"},{"issue":"1","key":"e_1_2_11_26_1","first-page":"102","article-title":"Persistent marked peripheral eosinophilia due to tuberculosis: A case report","volume":"42","author":"Garg G.","year":"2017","journal-title":"Iranian Journal of Medical Sciences"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0074-02762003000900023"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1722-1728.2001"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00098"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.46718-0"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.femsre.2005.04.013"},{"key":"e_1_2_11_33_1","unstructured":"Khan S. 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