Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-09-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3182931?pdf=render |
| _version_ | 1818133445834964992 |
|---|---|
| author | Sae Woong 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 |
| author_facet | Sae Woong 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 |
| author_sort | Sae Woong Park |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T08:52:51Z |
| format | Article |
| id | doaj.art-79f2ea7ff78e4942926faffb55966fd1 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T08:52:51Z |
| publishDate | 2011-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-79f2ea7ff78e4942926faffb55966fd12022-12-22T01:13:58ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742011-09-0179e100226410.1371/journal.ppat.1002264Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.Sae Woong ParkMarcus KlotzscheDaniel J WilsonHelena I BoshoffHyungjin EohUjjini ManjunathaAntje BlumenthalKyu RheeClifton E BarryCourtney C AldrichSabine EhrtDirk SchnappingerIn 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.http://europepmc.org/articles/PMC3182931?pdf=render |
| spellingShingle | Sae Woong 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 Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. PLoS Pathogens |
| title | Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. |
| title_full | Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. |
| title_fullStr | Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. |
| title_full_unstemmed | Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. |
| title_short | Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. |
| title_sort | evaluating the sensitivity of mycobacterium tuberculosis to biotin deprivation using regulated gene expression |
| url | http://europepmc.org/articles/PMC3182931?pdf=render |
| work_keys_str_mv | AT saewoongpark evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT marcusklotzsche evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT danieljwilson evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT helenaiboshoff evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT hyungjineoh evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT ujjinimanjunatha evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT antjeblumenthal evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT kyurhee evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT cliftonebarry evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT courtneycaldrich evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT sabineehrt evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression AT dirkschnappinger evaluatingthesensitivityofmycobacteriumtuberculosistobiotindeprivationusingregulatedgeneexpression |