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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Evaluating the sensitivity of mycobacterium tuberculosis to biotin deprivation using regulated gene expression
PLoS Pathogens, Volume 7, No. 9, Article e1002264, Year 2011
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Description
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, ΔbioA did not produce wild-type levels of biotinylated proteins, and therefore did not grow and lost viability. ΔbioA 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.
Authors & Co-Authors
Park, Sae Woong
United States, New York
Weill Cornell Medicine
Wilson, Daniel J.
United States, Minneapolis
University of Minnesota Twin Cities
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Eoh, Hyungjin
United States, New York
Weill Cornell Medicine
Manjunatha, Ujjini H.
Unknown Affiliation
Blumenthal, Antje
United States, New York
Weill Cornell Medicine
Barry, Clifton Earl
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Aldrich, Courtney C.
United States, Minneapolis
University of Minnesota Twin Cities
Ehrt, Sabine
United States, New York
Weill Cornell Medicine
Schnappinger, Dirk
United States, New York
Weill Cornell Medicine
Statistics
Citations: 117
Authors: 10
Affiliations: 3
Identifiers
Doi:
10.1371/journal.ppat.1002264
ISSN:
15537374
Research Areas
Genetics And Genomics
Health System And Policy
Infectious Diseases