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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
09:57

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

Published on: April 5, 2017

Evaluation of CoA biosynthesis proteins of Mycobacterium tuberculosis as potential drug targets

Anisha Ambady1, Disha Awasthy, Reena Yadav

  • 1AstraZeneca R & D, Infection iMed, Avishkar, Bellary Road, Hebbal, Bangalore, India.

Tuberculosis (Edinburgh, Scotland)
|September 8, 2012
PubMed

Insights

Coenzyme A pathway enzymes phosphopantetheine adenylyltransferase (CoaD) and dephospho CoA kinase (CoaE) are essential for Mycobacterium tuberculosis survival. Unique structural features offer potential for developing targeted inhibitors against this bacterium.

Area of Science:

  • Microbiology
  • Biochemistry
  • Drug Discovery

Background:

  • Coenzyme A (CoA) biosynthesis pathway proteins are potential targets for antimicrobial drug development.
  • Two key enzymes, phosphopantetheine adenylyltransferase (CoaD) and dephospho CoA kinase (CoaE), were investigated in Mycobacterium tuberculosis.
  • Previous studies suggested CoaD might be non-essential, necessitating further investigation.

Purpose of the Study:

  • To definitively determine the essentiality of CoaD and CoaE in Mycobacterium tuberculosis.
  • To assess the selectivity of these enzymes compared to their human counterparts.
  • To identify potential unique structural features for targeted inhibitor design.

Main Methods:

  • Gene inactivation studies in wild-type and merodiploid M. tuberculosis strains.
  • Reverse Transcription Polymerase Chain Reaction (RT-PCR) for gene transcription analysis.
  • Bioinformatics analysis including amino acid alignment, phylogenetic analysis, and structural comparison.

Main Results:

  • CoaD was confirmed as essential, requiring an additional gene copy for inactivation.
  • CoaE was also found to be essential for M. tuberculosis survival.
  • Both coaD and coaE genes are actively transcribed.
  • CoaD exhibits distant homology to human CoaD, while CoaE shows greater similarity to its human counterpart.
  • Unique amino acid residues were identified in M. tuberculosis CoaD and CoaE structures.

Conclusions:

  • CoaD and CoaE are essential enzymes for Mycobacterium tuberculosis.
  • Distinct structural features in M. tuberculosis CoaD and CoaE provide a basis for selective inhibitor development.
  • These enzymes represent promising targets for novel anti-tuberculosis therapies.

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