A5100685858- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Cancer therapeutics and mechanisms
- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Biochemical and Molecular Research
- Synthesis and biological activity
- Autophagy in Disease and Therapy
- Bacteriophages and microbial interactions
- Immune responses and vaccinations
- Pneumocystis jirovecii pneumonia detection and treatment
- Diagnosis and treatment of tuberculosis
- Adenosine and Purinergic Signaling
- Phenothiazines and Benzothiazines Synthesis and Activities
- Enzyme Structure and Function
- Calcium signaling and nucleotide metabolism
- RNA and protein synthesis mechanisms
- vaccines and immunoinformatics approaches
- COVID-19 Impact on Reproduction
- Immune Cell Function and Interaction
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Peptidase Inhibition and Analysis
- Quinazolinone synthesis and applications
- Vaccine Coverage and Hesitancy
- Essential Oils and Antimicrobial Activity
Translational Health Science and Technology Institute
2016-2025
Swami Vivekanand College of Pharmacy
2025
Delhi Pharmaceutical Science and Research University
2024
All India Institute of Medical Sciences Raipur
2024
All India Institute of Medical Sciences
2024
Central University of Punjab
2024
All India Institute of Medical Sciences Bhopal
2024
McMaster University
2022-2023
Regional Centre for Biotechnology
2022
Central Institute of Post-Harvest Engineering and Technology
2022
Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) converts PA-824 into three primary metabolites; major one corresponding des-nitroimidazole (des-nitro). When derivatives were used, amount des-nitro metabolite formed was highly correlated with anaerobic killing Mycobacterium tuberculosis (Mtb)....
Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether results integrating distally generated immunological signals vaccination/infection is unclear. Here we show subcutaneous Bacillus Calmette-Guérin (BCG) induce alveolar macrophages (AMs) lung. Although BCG trains...
Toxin–antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role physiology virulence. Nine these TA belong mazEF family, encoding intracellular MazF toxin its antitoxin, MazE. By overexpressing each nine putative homologues bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) Rv2801c (MazF9) induce bacteriostasis. The construction various single-, double- triple-mutant Mtb strains reveals...
In Escherichia coli, expression of the RelE and HipA toxins in absence their cognate antitoxins has been associated with generating multidrug-tolerant "persisters." Here we show that unlike persisters E. Mycobacterium tuberculosis selected one drug do not acquire cross-resistance to other classes drugs. M. three homologs arranged operons apparent antitoxins. Each toxin individually arrests growth both an effect is neutralized by coexpression antitoxin. Overexpression or deletion each had a...
Abstract In its myriad devastating forms, Tuberculosis (TB) has existed for centuries, and humanity is still affected by it. Mycobacterium tuberculosis ( M. ), the causative agent of TB, was foremost killer among infectious agents until COVID-19 pandemic. One key healthcare strategies available to reduce risk TB immunization with bacilli Calmette-Guerin (BCG). Although BCG been widely used protect against reports show that confers highly variable efficacy (0-80%) adult pulmonary TB....
Inorganic polyphosphate (polyP) is primarily synthesized by Polyphosphate Kinase-1 (PPK-1) and regulates numerous cellular processes, including energy metabolism, stress adaptation, drug tolerance, microbial pathogenesis. Here, we report that polyP interacts with acyl CoA carboxylases, enzymes involved in lipid biosynthesis Mycobacterium tuberculosis . We show deletion of ppk-1 M. results transcriptional metabolic reprogramming. In comparison to the parental strain, Δ mutant strain had...
Summary Protein tyrosine kinases and phosphatases from several bacterial pathogens have been shown to act as virulence factors by modulating the phosphorylation dephosphorylation of host proteins. The identification characterization two namely MptpA MptpB Mycobacterium tuberculosis has reported earlier. is secreted M. into extracellular mileu exhibits a pH optimum 5.6, similar lysosomal compartment cell. To determine role in pathogenesis , we constructed mptpB mutant strain homologous...
The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are only Mtb. We have synthesized analogues of both 4- explored their antitubercular activities. nitro group required for activities in all compounds. key determinants activity the 4-nitroimidazoles include bicyclic oxazine, lipophilic tail, 2-position oxygen. For 5-nitroimidazoles, neither corresponding analogue nor addition a tail conveyed...
Inorganic polyphosphate (polyP), a linear polymer of hundreds phosphate residues linked by ATP-like phosphoanhydride bonds, is found in all organisms and performs wide variety functions. This study shows that polyP accumulation occurs Mycobacterium tuberculosis upon exposure to various stress conditions. M. possesses single homolog ppk-1, we have disrupted ppk-1 the genome allelic replacement. The mutant strain exhibited negligible levels intracellular polyP, decreased expression sigF phoP,...
The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 represent a promising novel class of therapeutics for tuberculosis are currently in phase II clinical development. Both compounds pro-drugs that reductively activated by deazaflavin (F(420)) dependent nitroreductase (Ddn). Herein we describe the biochemical properties Ddn including optimal enzymatic turnover conditions substrate specificity. preference enzyme (S) isomer over (R) is directed presence long hydrophobic tail....
ABSTRACT HU, a widely conserved bacterial histone-like protein, regulates many genes, including those involved in stress response and virulence. Whereas ample data are available on HU-DNA communication, the knowledge how HU perceives signal transmit it to DNA remains limited. In this study, we identify HupB, homolog of human pathogen Mycobacterium tuberculosis , as component serine/threonine protein kinase (STPK) signaling. HupB is extracted its native state from exponentially growing cells...
Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored a refrigerated or frozen state prior to use. This is major impediment deployment resource-poor settings. Furthermore, several of them use viral vectors mRNA. In contrast protein subunit vaccines, there limited manufacturing expertise for these nucleic-acid-based modalities, especially the developing world. Neutralizing antibodies, clearest known correlate protection against SARS-CoV-2, primarily directed...
The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on excellent bactericidal properties aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position imidazole ring is required activity. Here, we show that substitution this by either nitrogen or sulfur yielded equipotent analogues. Acylating amino series, oxidizing thioether, replacing ether with carbon...
Background The variable efficacy (0–80%) of Mycobacterium bovis Bacille Calmette Guréin (BCG) vaccine against adult tuberculosis (TB) necessitates development alternative candidates. Development recombinant BCG (rBCG) over-expressing promising immunodominant antigens M. represents one the potential approaches for vaccines TB. Methods/Principal Findings A strain - rBCG85C, over expressing antigen 85C, a secretory immuno-dominant protein tuberculosis, was evaluated its protective in guinea...
Toxin-antitoxin (TA) systems are involved in diverse physiological processes prokaryotes, but their exact role Mycobacterium tuberculosis (Mtb) virulence and vivo stress adaptation has not been extensively studied. Here, we demonstrate that the VapBC11 TA module is essential for Mtb to establish infection guinea pigs. RNA-sequencing revealed overexpression of VapC11 toxin results metabolic slowdown, suggesting modulation growth rate an strategy survival. Interestingly, resulted upregulation...
Abstract Inorganic polyphosphate (PolyP) plays an essential role in microbial stress adaptation, virulence and drug tolerance. The genome of Mycobacterium tuberculosis encodes for two kinases (PPK-1, Rv2984 PPK-2, Rv3232c) polyphosphatases ( ppx-1 , Rv0496 ppx-2 Rv1026) maintenance intracellular PolyP levels. Microbial constitute a molecular mechanism, whereby microorganisms utilize as phosphate donor synthesis ATP. In the present study we have constructed ppk-2 mutant strain M. demonstrate...
New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by emergence drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as lead compound. 5NP-resistant isolates harbored mutations that were mapped fbiB and also resistant bicyclic nitroimidazole PA-824. Mechanistic studies confirmed 5NP is activated in an F420-dependent manner, resulting formation 1,10-phenanthroline...
Toxin-antitoxin (TA) systems are bicistronic genetic modules that ubiquitously present in bacterial genomes. The Mycobacterium tuberculosis genome encodes 90 putative TA systems, and these considered to be associated with maintenance of genomic stability or survival under unfavorable environmental conditions. majority M. have been annotated as belonging the virulence-associated protein B C (VapBC) family. However, their precise role physiology has not elucidated. Here, we functionally...
Alveolar Macrophages play a key role in the development of robust adaptive immune response against agent Tuberculosis (TB), Mycobacterium tuberculosis (M.tb). However, macrophage is often hampered by production IL-10, potent suppressor host response. The secretion IL-10 correlates with TB pathogenesis and persistence tissues. Concordantly, inhibition signaling, during BCG vaccination, confers higher protection M.tb through sustained Th1 Th17 responses. Therefore, uncovering effectors,...
Virulence-associated protein B and C toxin-antitoxin (TA) systems are widespread in prokaryotes, but their precise role physiology is poorly understood. We have functionally characterized the VapBC22 TA system from Mycobacterium tuberculosis. Transcriptome analysis revealed that overexpression of VapC22 toxin M. tuberculosis results reduced levels metabolic enzymes increased ribosomal proteins. Proteomics studies showed expression virulence-associated proteins cognate antitoxin, VapB22...