title: Targeting multiple response regulators of Mycobacterium tuberculosis augments the host immune response to infection.
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.
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Srijon Kaushik
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology &Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
authors.forename: Reshma
authors.initials: R
authors.lastname: Alokam
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Ayan
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Ranjeet
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Sanjaya Kumar
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700054, India.
authors.forename: Kuladip
authors.initials: K
authors.lastname: Jana
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad Gurgaon Expressway. Faridabad-121001, India.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Pharmacy, Birla Institute of Technology &Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology &Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; C480224:MprA protein, Mycobacterium tuberculosis; C100938:MtrA protein, Bacteria; C110608:RegX3 protein, Mycobacterium; D009569:Nitric Oxide; D004247:DNA