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Isoniazid and Host Immune System Interactions: A Proposal for a Novel Comprehensive Mode of Action

Isoniazid and Host Immune System Interactions: A Proposal for a Novel Comprehensive Mode of Action

Saifur R Khan, Yousef Manialawy, Arno G Siraki

Br J Pharmacol. 2019 Dec;176(24):4599-4608.

PMID: 31517993

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54853-A	Isoniazid		54-85-3	Price

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