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Targeting multiple response regulators of Mycobacterium tuberculosis augments the host immune response to infection
- Source :
- Scientific Reports
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- The genome of M. tuberculosis (Mtb) encodes eleven paired two component systems (TCSs) consisting of a sensor kinase (SK) and a response regulator (RR). The SKs sense environmental signals triggering RR-dependent gene expression pathways that enable the bacterium to adapt in the host milieu. We demonstrate that a conserved motif present in the C-terminal domain regulates the DNA binding functions of the OmpR family of Mtb RRs. Molecular docking studies against this motif helped to identify two molecules with a thiazolidine scaffold capable of targeting multiple RRs and modulating their regulons to attenuate bacterial replication in macrophages. The changes in the bacterial transcriptome extended to an altered immune response with increased autophagy and NO production, leading to compromised survival of Mtb in macrophages. Our findings underscore the promise of targeting multiple RRs as a novel yet unexplored approach for development of new anti-mycobacterial agents particularly against drug-resistant Mtb.
- Subjects :
- Models, Molecular
0301 basic medicine
030106 microbiology
Nitric Oxide
Genome
Article
Mycobacterium tuberculosis
Transcriptome
Mice
03 medical and health sciences
Immune system
Bacterial Proteins
Autophagy
Animals
Humans
Tuberculosis
Cells, Cultured
Genetics
Binding Sites
Multidisciplinary
biology
Gene Expression Profiling
Macrophages
DNA
biology.organism_classification
Cell biology
Molecular Docking Simulation
Gene expression profiling
Response regulator
RAW 264.7 Cells
Regulon
Mutation
ATP-Binding Cassette Transporters
Protein Binding
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....8a02682dbd2da95e901787bbe9797bf3