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Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.

TitleEvaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.
Publication TypeJournal Article
Year of Publication2011
AuthorsPark SWoong, Klotzsche M, Wilson DJ, Boshoff HI, Eoh H, Manjunatha U, Blumenthal A, Rhee K, Barry CE, Aldrich CC, Ehrt S, Schnappinger D
JournalPLoS Pathog
Volume7
Issue9
Paginatione1002264
Date Published2011 Sep
ISSN1553-7374
KeywordsAnimals, Bacterial Proteins, Biotin, Chronic Disease, Disease Models, Animal, Drug Delivery Systems, Mice, Mutation, Mycobacterium tuberculosis, Transaminases, Tuberculosis
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, 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.

DOI10.1371/journal.ppat.1002264
Alternate JournalPLoS Pathog
PubMed ID21980288
PubMed Central IDPMC3182931
Grant ListAI09179 / AI / NIAID NIH HHS / United States
R01 AI063446 / AI / NIAID NIH HHS / United States
AI063446 / AI / NIAID NIH HHS / United States
/ / Intramural NIH HHS / United States
/ / Wellcome Trust / United Kingdom

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