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

Sae Park, Marcus Klotzsche, Daniel J. Wilson, Helena I. Boshoff, Hyungjin Eoh, Ujjini Manjunatha, Antje Blumenthal, Kyu Rhee, Clifton E. Barry, Courtney C. Aldrich, Sabine Ehrt, Dirk Schnappinger

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

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.

Original languageEnglish (US)
Article numbere1002264
JournalPLoS Pathogens
Volume7
Issue number9
DOIs
StatePublished - Sep 2011

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