Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone

@article{Grzegorzewicz2015CovalentMO,
  title={Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone},
  author={Anna E. Grzegorzewicz and Nathalie Eynard and Annaïk Quémard and E Jeffrey North and Alyssa Margolis and Jared J. Lindenberger and Victoria C Jones and Jana Kordul{\'a}kov{\'a} and Patrick Joseph Brennan and Richard E. Lee and Donald R. Ronning and Michael R. McNeil and Mary Jackson},
  journal={ACS Infectious Diseases},
  year={2015},
  volume={1},
  pages={91 - 97}
}
Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and… 
Mechanisms of resistance associated with the inhibition of the dehydration step of FAS-II in Mycobacterium tuberculosis.
TLDR
The results highlight the importance of developing optimized inhibitors of the dehydration step of FAS-II capable of inhibiting both dehydratases simultaneously, a goal that may be achievable given the structural resemblance of the two enzymes and their reliance on the same catalytic subunit, HadB.
Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives
TLDR
In this work, in vitro the effect of the thiourea drug isoxyl on six epoxide hydrolases of M. tuberculosis is studied using a fatty acid substrate and it is shown that one of the proteins inhibited is EphD, an enzyme involved in the metabolism of mycolic acids, key components of the mycobacterial cell wall.
Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis β-ketoacyl-acyl carrier protein reductase MabA.
TLDR
High-resolution crystal structures of MabA from Mycobacterium smegmatis in its apo, NADP+-bound and NADPH-bound forms are reported and reveal the structural reorganization of the lid region covering the active site of the enzyme.
Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
TLDR
Rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) revealed some compounds exhibited promising antitubercular activity and theoretical calculations were established to predict the physicochemical properties of the most active compounds.
Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea.
TLDR
The effective compounds synthesized showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in 14C-radiolabelled assay and executed their potent immunomodulatory activity by up-regulation of IFN-γ and IL-12 and down- regulation of IL-10.
New Insights into the Mycolate-Containing Compound Biosynthesis and Transport in Mycobacteria.
TLDR
Beyond the more accurate picture of the biosynthesis and translocation pathways dedicated to these unique molecules, major issues that should be addressed in the future are also discussed.
Preparation and Antitubercular Activities of Palindromic Hydrazinecarbothioamides and Carbonothioic Dihydrazides
With approximately one-third of the world’s population infected, tuberculosis continues to be a global public health crisis. The rise of strains that are unusually virulent or highly resistant to
Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384
TLDR
This study uncovered a new mechanism of drug resistance in M. abscessus and demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates against M.Abscessus infections.
Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance
TLDR
Identification of the prodrugs targets and a better understanding of their modes of action and also of their activation mechanisms are of crucial importance, as well as the reported resistance related to these mechanisms of activation/action.
The Non-Essential Mycolic Acid Biosynthesis Genes hadA and hadC Contribute to the Physiology and Fitness of Mycobacterium smegmatis
TLDR
The present study shows that M. smegmatis cells remain viable in the absence of either HadA and HadC or both, and shows that the hadC mutants are significantly more susceptible to low- and high-temperature and to selective toxic compounds, including several current anti-tubercular drugs.
...
1
2
3
...

References

SHOWING 1-10 OF 38 REFERENCES
A Common Mechanism of Inhibition of the Mycobacterium tuberculosis Mycolic Acid Biosynthetic Pathway by Isoxyl and Thiacetazone*
TLDR
It is shown that treating M. tuberculosis with ISO or TAC results in both cases in the accumulation of 3-hydroxy C18, C20, and C22 fatty acids, suggestive of an inhibition of the dehydratase step of the fatty-acid synthase type II elongation cycle.
Isoxyl Activation Is Required for Bacteriostatic Activity against Mycobacterium tuberculosis
TLDR
It is demonstrated for the first time that the EthA-mediated oxidation of ISO is absolutely required for this prodrug to inhibit its lethal enzymatic target(s) in M. tuberculosis.
Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3.
TLDR
It is reported here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites and these reactions may contribute to the antitubercular activity and/or toxicity of TAZ.
The Mycobacterium Tuberculosis FAS-II Dehydratases and Methyltransferases Define the Specificity of the Mycolic Acid Elongation Complexes
TLDR
The analysis of the composition and architecture of the interactome between the known components of the Mtb FAS-II complexes showed that the recently identified dehydratases HadAB and HadBC are part of the Fas-II elongation complexes and may represent a specific link between the core of FAS -II and the condensing enzymes of the system.
EthA, a Common Activator of Thiocarbamide-Containing Drugs Acting on Different Mycobacterial Targets
TLDR
Evidence is provided that EthA, previously shown to activate ethionamide, also converts isoxyl (ISO) and thiacetazone (TAC) into reactive species, which suggests thatEthA is a common activator of thiocarbamide-containing drugs.
Mutations in the essential FAS II β‐hydroxyacyl ACP dehydratase complex confer resistance to thiacetazone in Mycobacterium tuberculosis and Mycobacterium kansasii
It has recently been shown that the anti‐mycobacterial pro‐drug thiacetazone (TAC) inhibits the conversion of double bonds of mycolic acid precursors into cyclopropyl rings in Mycobacterium bovis var
Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis
TLDR
This study reports isolation of spontaneous mutants in Mycobacterium bovis BCG that are highly resistant to TAC, but carry a functional EthA, and provides novel mechanistic insights into antitubercular drug activation by co‐ordinated actions of EthA and MmaA4.
Point Mutations within the Fatty Acid Synthase Type II Dehydratase Components HadA or HadC Contribute to Isoxyl Resistance in Mycobacterium tuberculosis
TLDR
It is found that point mutations in either the HadA or HadC component of the type II fatty acid synthase (FAS-II) are associated with increased levels of resistance to ISO in Mycobacterium tuberculosis.
The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis.
TLDR
In vivo analysis confirmed that overexpression of each of the four mutant KasAs enhanced isoniazid resistance when compared to overeexpression of wild-type KasA, and suggest discrete anabolic roles for both KasA and KasB in mycolic acid synthesis and substantiate the involvement of KasA mutations in isoniaZid resistance.
Protein–protein interactions within the Fatty Acid Synthase‐II system of Mycobacterium tuberculosis are essential for mycobacterial viability
TLDR
It is shown by a transdominant genetic approach that these mutants are dominant negative in both non‐pathogenic and pathogenic mycobacteria, an important step towards the design of a new generation of anti‐tuberculous agents, as being inhibitors of essential protein–protein interactions.
...
1
2
3
4
...