Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1002264
Title: Evaluating the sensitivity of mycobacterium tuberculosis to biotin deprivation using regulated gene expression
Authors: Park S.
Klotzsche M.
Wilson D.J.
Boshoff H.I.
Eoh H.
Manjunatha U. 
Blumenthal A.
Rhee K.
Barry C.E.
Aldrich C.C.
Ehrt S.
Schnappinger D.
Keywords: 7,8 diaminopelargonic acid synthase
anhydrotetracycline
biotin
biotin derivative
doxycycline
unclassified drug
aminotransferase
bacterial protein
BioA protein, bacteria
animal experiment
animal model
animal tissue
article
bacterial growth
bacterial viability
biotinylation
controlled study
enzyme activity
gene expression regulation
gene silencing
in vitro study
in vivo study
mouse
Mycobacterium tuberculosis
nonhuman
protein synthesis
quantitative analysis
sensitivity analysis
signal transduction
tuberculosis
wild type
animal
biosynthesis
chronic disease
disease model
drug delivery system
enzymology
genetics
metabolism
methodology
mutation
tuberculosis
Bacteria (microorganisms)
Murinae
Mus
Mycobacterium tuberculosis
Animals
Bacterial Proteins
Biotin
Chronic Disease
Disease Models, Animal
Drug Delivery Systems
Mice
Mutation
Mycobacterium tuberculosis
Transaminases
Tuberculosis
Issue Date: 2011
Citation: Park S., Klotzsche M., Wilson D.J., Boshoff H.I., Eoh H., Manjunatha U., Blumenthal A., Rhee K., Barry C.E., Aldrich C.C., Ehrt S., Schnappinger D. (2011). Evaluating the sensitivity of mycobacterium tuberculosis to biotin deprivation using regulated gene expression. PLoS Pathogens 7 (9) : e1002264. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1002264
Abstract: In the search for new drug targets, we evaluated the biotin synthetic pathway of Mycobacterium tuberculosis (Mtb) and constructed an Mtb mutant lacking the biotin biosynthetic enzyme 7,8-diaminopelargonic acid synthase, BioA. In biotin-free synthetic media, ?bioA did not produce wild-type levels of biotinylated proteins, and therefore did not grow and lost viability. ?bioA was also unable to establish infection in mice. Conditionally-regulated knockdown strains of Mtb similarly exhibited impaired bacterial growth and viability in vitro and in mice, irrespective of the timing of transcriptional silencing. Biochemical studies further showed that BioA activity has to be reduced by approximately 99% to prevent growth. These studies thus establish that de novo biotin synthesis is essential for Mtb to establish and maintain a chronic infection in a murine model of TB. Moreover, these studies provide an experimental strategy to systematically rank the in vivo value of potential drug targets in Mtb and other pathogens. © 2011 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/161652
ISSN: 15537366
DOI: 10.1371/journal.ppat.1002264
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