1. Targeting multiple response regulators of Mycobacterium tuberculosis augments the host immune response to infection
- Author
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Reshma Alokam, Ranjeet Kumar, Arun Kumar Sharma, Perumal Yogeeswari, Joyoti Basu, Ayan Chatterjee, Manikuntala Kundu, Sanjaya Kumar Sahu, Dharmarajan Sriram, Srijon Kaushik Banerjee, Manish Kumar, Kuladip Jana, and Ramandeep Singh
- 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 - 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.
- Published
- 2016