Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action

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.

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

“…Furthermore, according to the calculated LogP values, the compounds are highly lipophilic compared to INH (LogP = −0.35, calculated in SwissADME). Besides mutations in either katG or the inhA promoter, this low hydrophobicity of INH is linked to the long duration of TB treatment [ 32 ]. The mycolic acid outer layer of Mtb is so lipophilic that INH cannot efficiently penetrate and cross it.…”

LncRNA DANCR restrained the survival of mycobacterium tuberculosis H37Ra by sponging miR-1301-3p/miR-5194

“…Unfortunately, this type of process provides chances for M. tuberculosis to manipulate autophagy. Studies have revealed that once innate immune cells are phagocytized by M. tuberculosis , the proton pump on the cell membrane decreases due to the influence of the bacterial surface proteins, resulting in the reduction of H + influx and a less acidic environment, which provides a suitable environment for M. tuberculosis parasitization ( Khan et al, 2019 ). Another study showed that after invading the human body, M. tuberculosis leads to a fat metabolism disorder in macrophages, and the abnormally increased lipid droplet ingestion by autophagosomes was found to co-locate with M. tuberculosi s and become the nutrient source for its long-term parasitism ( Ouimet et al, 2016 ).…”

Immune priming in Armadillidium vulgare against Salmonella enterica: direct or indirect costs on life history traits?

“…Although immune priming is advantageous in terms of survival ability, its expression could be costly for individuals, particularly when it relies on the long-lasting sustained immune response ( Moret 2003 ; Contreras-Garduño et al 2014 , 2019 ; Coustau et al 2016 ; Shikano et al 2016 ; Khan et al 2019 ). According to the theory of life-history traits, organisms must allocate their limited energy to different biological functions by making trade-offs.…”