Essential metabolites of mycobacterium tuberculosis and their mimics

Gyanu Lamichhane, Joel S. Freundlich, Sean Ekins, Niluka Wickramaratne, Scott T. Nolan, William Ramses Bishai

Research output: Contribution to journalArticle

Abstract

An organism requires a range of biomolecules for its growth. By definition, these are essential molecules which constitute the basic metabolic requirements of an organism. A small organic molecule with chemical similarity to that of an essential metabolite may bind to the enzyme that catalyzes its production and inhibit it, likely resulting in the stasis or death of the organism. Here, we report a high-throughput approach for identifying essential metabolites of an organism using genetic and biochemical approaches and then implement computational approaches to identify metabolite mimics. We generated and genotyped 5,126 Mycobacterium tuberculosis mutants and performed a statistical analysis to determine putative essential genes. The essential molecules of M. tuberculosis were classified as products of enzymes that are encoded by genes in this list. Although incomplete, as many enzymes of M. tuberculosis have yet to be identified and characterized, this is the first report of a large number of essential molecules of the organism. We identified essential metabolites of three distinct metabolic pathways in M. tuberculosis and selected molecules with chemical similarity using cheminformatics strategies that illustrate a variety of different pharmacophores. Our approach is aimed at systematic identification of essential molecules and their mimics as a blueprint for development of effective chemical probes of M. tuberculosis metabolism, with the ultimate goal of seeking drugs that can kill this pathogen. As an illustration of this approach, we report that compounds JFD01307SC and L-methionine-S-sulfoximine, which share chemical similarity with an essential molecule of M. tuberculosis, inhibited the growth of this organism at micromolar concentrations.

Original languageEnglish (US)
JournalmBio
Volume2
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Mycobacterium tuberculosis
Enzymes
Methionine Sulfoximine
Essential Genes
Growth
Metabolic Networks and Pathways
Methionine
Molecular Biology
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Essential metabolites of mycobacterium tuberculosis and their mimics. / Lamichhane, Gyanu; Freundlich, Joel S.; Ekins, Sean; Wickramaratne, Niluka; Nolan, Scott T.; Bishai, William Ramses.

In: mBio, Vol. 2, No. 1, 01.2011.

Research output: Contribution to journalArticle

Lamichhane, Gyanu ; Freundlich, Joel S. ; Ekins, Sean ; Wickramaratne, Niluka ; Nolan, Scott T. ; Bishai, William Ramses. / Essential metabolites of mycobacterium tuberculosis and their mimics. In: mBio. 2011 ; Vol. 2, No. 1.
@article{b36dcb52ea9e437d8b9dd15840fc7ce0,
title = "Essential metabolites of mycobacterium tuberculosis and their mimics",
abstract = "An organism requires a range of biomolecules for its growth. By definition, these are essential molecules which constitute the basic metabolic requirements of an organism. A small organic molecule with chemical similarity to that of an essential metabolite may bind to the enzyme that catalyzes its production and inhibit it, likely resulting in the stasis or death of the organism. Here, we report a high-throughput approach for identifying essential metabolites of an organism using genetic and biochemical approaches and then implement computational approaches to identify metabolite mimics. We generated and genotyped 5,126 Mycobacterium tuberculosis mutants and performed a statistical analysis to determine putative essential genes. The essential molecules of M. tuberculosis were classified as products of enzymes that are encoded by genes in this list. Although incomplete, as many enzymes of M. tuberculosis have yet to be identified and characterized, this is the first report of a large number of essential molecules of the organism. We identified essential metabolites of three distinct metabolic pathways in M. tuberculosis and selected molecules with chemical similarity using cheminformatics strategies that illustrate a variety of different pharmacophores. Our approach is aimed at systematic identification of essential molecules and their mimics as a blueprint for development of effective chemical probes of M. tuberculosis metabolism, with the ultimate goal of seeking drugs that can kill this pathogen. As an illustration of this approach, we report that compounds JFD01307SC and L-methionine-S-sulfoximine, which share chemical similarity with an essential molecule of M. tuberculosis, inhibited the growth of this organism at micromolar concentrations.",
author = "Gyanu Lamichhane and Freundlich, {Joel S.} and Sean Ekins and Niluka Wickramaratne and Nolan, {Scott T.} and Bishai, {William Ramses}",
year = "2011",
month = "1",
doi = "10.1128/mBio.00301-10",
language = "English (US)",
volume = "2",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Essential metabolites of mycobacterium tuberculosis and their mimics

AU - Lamichhane, Gyanu

AU - Freundlich, Joel S.

AU - Ekins, Sean

AU - Wickramaratne, Niluka

AU - Nolan, Scott T.

AU - Bishai, William Ramses

PY - 2011/1

Y1 - 2011/1

N2 - An organism requires a range of biomolecules for its growth. By definition, these are essential molecules which constitute the basic metabolic requirements of an organism. A small organic molecule with chemical similarity to that of an essential metabolite may bind to the enzyme that catalyzes its production and inhibit it, likely resulting in the stasis or death of the organism. Here, we report a high-throughput approach for identifying essential metabolites of an organism using genetic and biochemical approaches and then implement computational approaches to identify metabolite mimics. We generated and genotyped 5,126 Mycobacterium tuberculosis mutants and performed a statistical analysis to determine putative essential genes. The essential molecules of M. tuberculosis were classified as products of enzymes that are encoded by genes in this list. Although incomplete, as many enzymes of M. tuberculosis have yet to be identified and characterized, this is the first report of a large number of essential molecules of the organism. We identified essential metabolites of three distinct metabolic pathways in M. tuberculosis and selected molecules with chemical similarity using cheminformatics strategies that illustrate a variety of different pharmacophores. Our approach is aimed at systematic identification of essential molecules and their mimics as a blueprint for development of effective chemical probes of M. tuberculosis metabolism, with the ultimate goal of seeking drugs that can kill this pathogen. As an illustration of this approach, we report that compounds JFD01307SC and L-methionine-S-sulfoximine, which share chemical similarity with an essential molecule of M. tuberculosis, inhibited the growth of this organism at micromolar concentrations.

AB - An organism requires a range of biomolecules for its growth. By definition, these are essential molecules which constitute the basic metabolic requirements of an organism. A small organic molecule with chemical similarity to that of an essential metabolite may bind to the enzyme that catalyzes its production and inhibit it, likely resulting in the stasis or death of the organism. Here, we report a high-throughput approach for identifying essential metabolites of an organism using genetic and biochemical approaches and then implement computational approaches to identify metabolite mimics. We generated and genotyped 5,126 Mycobacterium tuberculosis mutants and performed a statistical analysis to determine putative essential genes. The essential molecules of M. tuberculosis were classified as products of enzymes that are encoded by genes in this list. Although incomplete, as many enzymes of M. tuberculosis have yet to be identified and characterized, this is the first report of a large number of essential molecules of the organism. We identified essential metabolites of three distinct metabolic pathways in M. tuberculosis and selected molecules with chemical similarity using cheminformatics strategies that illustrate a variety of different pharmacophores. Our approach is aimed at systematic identification of essential molecules and their mimics as a blueprint for development of effective chemical probes of M. tuberculosis metabolism, with the ultimate goal of seeking drugs that can kill this pathogen. As an illustration of this approach, we report that compounds JFD01307SC and L-methionine-S-sulfoximine, which share chemical similarity with an essential molecule of M. tuberculosis, inhibited the growth of this organism at micromolar concentrations.

UR - http://www.scopus.com/inward/record.url?scp=79953700626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953700626&partnerID=8YFLogxK

U2 - 10.1128/mBio.00301-10

DO - 10.1128/mBio.00301-10

M3 - Article

C2 - 21285434

AN - SCOPUS:79953700626

VL - 2

JO - mBio

JF - mBio

SN - 2161-2129

IS - 1

ER -