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Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action
Author(s) -
Khan Saifur R.,
Manialawy Yousef,
Siraki Arno G.
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14867
Subject(s) - isoniazid , mycobacterium tuberculosis , microbiology and biotechnology , mode of action , tuberculosis , immune system , antibiotics , biology , chemistry , immunology , medicine , biochemistry , pathology
The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase–peroxidase enzyme KatG in Mycobacterium tuberculosis ( Mtb ). This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent Mtb 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‐inflammatory monocytes and providing protection against reactive species‐induced “self‐necrosis” of phagocytes. In the case of active TB, different immune cells form INH‐NAD + adducts to inhibit Mtb 's cell wall biosynthesis. This additionally suggests that the antibacterial properties of INH do not rely on KatG of Mtb . As such, isoniazid‐resistant TB needs to be re‐evaluated.