Abstract:
:Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy. This review describes the serendipitous discovery of INH, its effectiveness on TB patients, and early studies to discover its mechanisms of bacteriocidal activity. Forty years after its introduction as a TB drug, the development of gene transfer in mycobacteria enabled the discovery of the genes encoding INH resistance, namely, the activator (katG) and the target (inhA) of INH. Further biochemical and x-ray crystallography studies on KatG and InhA proteins and mutants provided comprehensive understanding of INH mode of action and resistance mechanisms. Bacterial cultures can harbor subpopulations that are genetically or phenotypically resistant cells, the latter known as persisters. Treatment of exponentially growing cultures of M. tuberculosis with INH reproducibly kills 99% to 99.9% of cells in 3 days. Importantly, the surviving cells are slowly replicating or non-replicating cells expressing a unique stress response signature: these are the persisters. These persisters can be visualized using dual-reporter mycobacteriophages and their formation prevented using reducing compounds, such as N-acetylcysteine or vitamin C, that enhance M. tuberculosis' respiration. Altogether, this review portrays a detailed molecular analysis of INH killing and resistance mechanisms including persistence. The phenomenon of persistence is clearly the single greatest impediment to TB control, and research aimed at understanding persistence will provide new strategies to improve TB chemotherapy.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Vilchèze C,Jacobs WR Jrdoi
10.1016/j.jmb.2019.02.016subject
Has Abstractpub_date
2019-08-23 00:00:00pages
3450-3461issue
18eissn
0022-2836issn
1089-8638pii
S0022-2836(19)30093-2journal_volume
431pub_type
杂志文章,评审abstract::RNA localization is an important means of post-transcriptional regulation of gene expression in many eukaryotic cell types. In neurons, select RNAs are delivered to postsynaptic dendritic microdomains, a mechanism that is considered a key underpinning in the administration of long-term synaptic plasticity. BC1 RNA is ...
journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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doi:10.1006/jmbi.1994.1336
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journal_title:Journal of molecular biology
pub_type: 杂志文章
doi:10.1006/jmbi.1993.1325
更新日期:1993-06-05 00:00:00
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abstract::A novel virus, ATV, of the hyperthermophilic archaeal genus Acidianus has the unique property of undergoing a major morphological development outside of, and independently of, the host cell. Virions are extruded from host cells as lemon-shaped tail-less particles, after which they develop long tails at each pointed en...
journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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