Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid

@article{Argyrou2006MycobacteriumTD,
  title={Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid},
  author={Argyrides Argyrou and Matthew W. Vetting and Bola Aladegbami and John S Blanchard},
  journal={Nature Structural \&Molecular Biology},
  year={2006},
  volume={13},
  pages={408-413}
}
Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD+ and NADP+ to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of… 
Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid
TLDR
The dfrA overexpression experiments conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH, and 14 other overexpressed proteins that have been proposed to bind some form of InH-NAD(P) adduct are not found.
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TLDR
The Mycobacterium tuberculosis proteome is profiled using both the INH-NAD and INH -NADP adducts coupled to solid supports and identified, in addition to InhA and DfrA, 16 other proteins that bind these adductS with high affinity, the majority of these are predicted to be pyridine nucleotide-dependent dehydrogenases/reductases.
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TLDR
The 4-isonicotinoylnicotinamide observed in human urine samples is likely derived from the degradation of oxidized INH-NAD adducts and provides direct evidence of host INH activation.
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TLDR
Each known mechanism of resistance to INH and ETH is described and its importance in M. tuberculosis clinical isolates is described.
Antibiotic Resistance in Mycobacterium tuberculosis
TLDR
In the resting mutant enzyme, a rapid evolution of 5-c heme to 6-c species occurred in contrast with the behavior of WT KatG and KatG[S315T] and consistent with greater flexibility at the heme edge in the absence of the hydroxyl of residue 315.
Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis
TLDR
Interestingly, a similar ligand‐induced conformational change is also observed for the InhA mutants, indicating that the mutations modulate communication between the subunits without affecting the two conformational states of the protein that are present.
High-throughput Screening and Sensitized Bacteria Identify an M. tuberculosis Dihydrofolate Reductase Inhibitor with Whole Cell Activity
TLDR
The results demonstrate the potential to identify Mtb DHFR inhibitors with activity against whole cells, and indicate the power of using a recombinant strain of Mtb expressing lower levels of DHFR to facilitate the discovery of antimycobacterial agents.
Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates.
TLDR
The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates, as well as the affinities of diaverdine and methotrexate.
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