Biochemie des Isoniazids

Krüger-Thiemer, Ekkehard

doi:10.1007/978-3-662-30612-3_7

Cited by 21 publications

(6 citation statements)

References 310 publications

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“…Thus, the observed lack of contribution of the mycolate layer in the transport of INH could be explained by either a diffusion of INH through the recently characterized porin‐like OmpATb of M. tuberculosis (Senaratne et al ., 1998) or, alternatively, by the potential intrinsic high diffusion of the molecule through membranes. INH is a small water‐soluble molecule which is not ionized between pH 6 and pH 9 (Krüger‐Thiemer, 1956), two properties that confer upon INH a good diffusibility through cell barriers. Thus, this possibility was tested by comparing the diffusion of INH and glycerol through liposomes made from phosphatidylcholine and phosphatidylglycerol.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope

Jackson

Raynaud

Lanéelle

et al. 1999

Molecular Microbiology

250

267

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SummaryThe antigen 85 complex of Mycobacterium tuberculosis consists of three abundantly secreted proteins. The recent characterization of a mycoloyltransferase activity associated in vitro with each of these antigens suggested that they are potentially important for the building of the unusual cell envelope of mycobacteria. To define the physiological role of these proteins, the gene coding for antigen 85C was inactivated by transposon mutagenesis. The resulting mutant was shown to transfer 40% fewer mycolates to the cell wall with no change in the types of mycolates esterifying arabinogalactan or in the composition of non-covalently linked mycolates. As a consequence, the diffusion of the hydrophobic chenodeoxycholate and the hydrophilic glycerol, but not that of isoniazid, was found to be much faster through the cell envelope of the mutant than that of the parent strain. Taken together, these data demonstrate that: (i) antigen 85C is involved directly or indirectly in the transfer of mycolates onto the cell wall of the whole bacterium; (ii) the enzyme is not specific for a given type of mycolate; and (iii) the cell wall-linked mycolate layer may represent a barrier for the diffusion of small hydrophobic and hydrophilic molecules.

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Section: Resultsmentioning

confidence: 99%

Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope

Jackson

Raynaud

Lanéelle

et al. 1999

Molecular Microbiology

250

267

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“…An alternative hypothesis had been put forward by Krüger-Thiemer [69][70][71] and is depicted in Figure 5. It suggests that INH enters the mycobacterium by passive diffusion, facilitated by the hydrazide.…”

Section: The Active Form Of Isoniazid Including Stereo-chemical Aspectsmentioning

confidence: 97%

“…2002, 335, 511-525 Figure 5. Isonicotinic acid hypothesis [21,22,69,70,72,76]. ic acyl group of the incoming adduct stereospecifically replaces the (4S)-hydrogen atom in the NADH moiety (see asterisks (*) in Figure 1 and 4).…”

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confidence: 99%

Antitubercular Isoniazid and Drug Resistance of Mycobacterium tuberculosis — A Review

Scior

Morales

Eisele

et al. 2002

Archiv der Pharmazie

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Isoniazid is one of the most potent drugs available for tuberculosis treatment. As a pro-drug it requires activation, which is performed by catalase/peroxidase. The active principle, whose identity has not yet been determined unambiguously, then acts on at least one target molecule, the enoyl-acyl carrier protein, required for the synthesis of the vital mycolic acids present in the cell wall of the bacterium. Some other targets have been proposed in order to explain the unusual potency of isoniazid; however, the supporting data are still controversial. We thoroughly discuss the action of isoniazid, resistance mechanisms, and the possible active product, which includes an isonicotinic acid-NADH adduct as well as a meta-isomer of NADH. Both structures have been probed positively in a 3D modeling analysis.

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“…However, neither the mode of action of this drug nor the origin of the high sensitivity of Mycobacterium tuberculosis towards it is well understood. Most of the current models of the uptake and action of INH in M. tuberculosis are based on its chemical transformation by a catalase- peroxidase, now named KatG (for a review see Zhang & Young, 1993), a model first introduced by E. Krüger-Thiemer and colleagues (Kriiger-Thiemer, 1957). It is currently postulated that INH is a prodrug which is active after transformation by the peroxidase into radicals that can either react with vital targets in mycobacterial cells, or ultimately produce isonicotinic acid (Johnsson & Schultz, 1994; Marcinkeviciene et al, 1995; Shoeb et al, 1985a), explaining INH resistance of KatG-defective mutants.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of isoniazid uptake in Mycobacterium tuberculosis

et al. 1998

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Initial transport kinetics of isoniazid (INH) and its uptake a t the plateau were studied in Mycobacterium tuberculosis H37Rv under various experimental conditions. The initial uptake velocity increased linearly with INH concentration from 2 x lom6 M to M. It was modified neither by addition of a protonophore that abolished proline transport, nor following ATP depletion by arsenate, which inhibited glycerol uptake, two transport processes taken as controls for secondary active transport and facilitated diffusion, respectively. Microaerobiosis or low temperature (4 "C) were without effect on initial uptake. It is thus likely that INH transport in M. tuberculosis proceeds by a passive diffusion mechanism, and that catalase-peroxidase (KatG) is not involved in the actual transport. However, conditions inhibiting KatG activity (high INH concentration, microaerobiosis, low temperature) decrease cell radioactivity a t the uptake plateau. It is proposed that INH transport occurs by passive diffusion. KatG is involved only in the intracellular accumulation of oxidized derivatives of INH, especially of isonicotinic acid, which is trapped inside cells in its ionized form. This model explains observed and previously known characteristics of the accumulation of radioactivity in the presence of [14C]INH for various species and strains of mycobacteria.

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Biochemie des Isoniazids

Cited by 21 publications

References 310 publications

Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope

Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope

Antitubercular Isoniazid and Drug Resistance of Mycobacterium tuberculosis — A Review

Mechanism of isoniazid uptake in Mycobacterium tuberculosis

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