A5072785188- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Mycobacterium research and diagnosis
- RNA and protein synthesis mechanisms
- Antibiotic Resistance in Bacteria
- Phenothiazines and Benzothiazines Synthesis and Activities
- Biochemical and Molecular Research
- Calcium signaling and nucleotide metabolism
- Plant Micronutrient Interactions and Effects
- Antifungal resistance and susceptibility
- PARP inhibition in cancer therapy
- Antibiotics Pharmacokinetics and Efficacy
- Fungal Infections and Studies
- vaccines and immunoinformatics approaches
- Peptidase Inhibition and Analysis
- Magnetic and Electromagnetic Effects
- Crop Yield and Soil Fertility
- Pneumocystis jirovecii pneumonia detection and treatment
- Biochemical and Structural Characterization
Centre for DNA Fingerprinting and Diagnostics
2019-2025
University of Hyderabad
2020-2021
AstraZeneca (India)
2013-2019
AstraZeneca (United Kingdom)
2012
We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy mouse models. The series emerged from scaffold morphing efforts was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-D-ribose2'-epimerase (DprE1). With "drug-like" properties no expectation of pre-existing resistance the clinic, this chemical has potential be developed therapy for drug-sensitive drug-resistant tuberculosis.
New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global (TB) threat. Toward this end, we previously reported identification of 1,4-azaindoles, a promising class compounds with potent antitubercular activity through noncovalent inhibition decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). Further, series was optimized improve its physicochemical properties pharmacokinetics in...
The cell envelope of Mycobacterium tuberculosis contains glycans and lipids peculiar structure that play prominent roles in the biology pathogenesis tuberculosis. Consequently, chemical biosynthesis wall have been intensively investigated order to identify novel drug targets. Here, we validate function phosphatidyl-myo-inositol mannosyltransferase PimA is vital for M. vitro vivo. initiates mannosides by transferring a mannosyl residue from GDP-Man on cytoplasmic side plasma membrane. To...
We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of 1,4-azaindole series. The clinical progression the series our previous work validates potential exploring newer chemical entities with antimycobacterial activity driven via noncovalent inhibition decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). representative compounds new reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent...
Robust and physiologically relevant infection models are required to investigate pharmacokinetic-pharmacodynamic (PK/PD) correlations for anti-tuberculosis agents at preclinical discovery. We have validated an inhalation-based rat model of tuberculosis harbouring mycobacteria in a replicating state, that is suitable investigating pharmacokinetics drug action anti-tubercular agents. A reproducible actively lung was established Wistar rats by inhalation series graded inocula Mycobacterium...
Coadministration of moxifloxacin and rifampin was evaluated in a murine model Mycobacterium tuberculosis pulmonary infection to determine whether the finding antagonism documented hollow-fiber could be recapitulated vivo. Colony counts were followed no-treatment control group, groups administered or monotherapy, group combination two agents. Following 18 days once-daily oral administration mice infected with M. tuberculosis, there reduction plasma exposure that decreased further when...
Secretory proteins are key modulators of host–pathogen interaction. The human opportunistic fungal pathogen Candida glabrata lacks secreted proteolytic activity but possesses 11 glycosylphosphatidylinositol-anchored aspartyl proteases, also referred to as Yapsins (CgYps1–11), that essential for its virulence. To delineate the role CgYapsins in interaction with host cells, we have profiled, through liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, total secretome wild-type...
P128 is a chimeric anti-staphylococcal protein having catalytic domain from Staphylococcus bacteriophage K tail associated structural and cell wall targeting the bacteriocin-lysostaphin. In this study, we disclose additional properties of compared same with lysostaphin. While lysostaphin was found to get inactivated by heat inactive on its parent strain S. simulans biovar staphylolyticus, thermostable lytic towards staphylolyticus demonstrating difference in their mechanism action. Selected...
AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration AZD5847 to mice infected M. tuberculosis H37Rv in chronic-infection model resulted 1.0-log10 reduction the lung CFU count after 4 weeks treatment at daily area under concentration-time curve (AUC) 105 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success acute-infection...
ABSTRACT There are currently 18 drug classes for the treatment of tuberculosis, including those in development pipeline. An silico simulation enabled combing innumerably large search space to derive multidrug combinations. Through use ordinary differential equations (ODE), we constructed an kinetic platform which major metabolic pathways Mycobacterium tuberculosis and mechanisms antituberculosis drugs were integrated into a virtual proteome. The optimized model was used evaluate 816 triplets...
One of the major impediments in anti-tubercular drug discovery is lack a robust grammar that governs in-vitro to in-vivo translation efficacy. Mycobacterium tuberculosis (Mtb) capable growing both extracellular as well intracellular; encountering various hostile conditions like acidic milieu, free radicals, starvation, oxygen deprivation, and immune effector mechanisms. Unique survival strategies Mtb have prompted researchers develop equivalents simulate physiologies exploited find...
Abstract Many bacteriophages modulate the host transcription machinery for efficient expression of their own genomes. Phage P4 polarity suppression protein, Psu, is a building block viral capsid and inhibits hexameric termination factor, ρ, by presently unknown mechanisms. We elucidated cryogenic electron microscopy structures ρ-Psu complexes, showing that Psu dimers laterally clamp two inactive, open ρ rings promote expansion to higher-oligomeric states. Systematic ATPase, nucleotide...
Aims To characterize the 21-kDa iron-regulated cell wall protein in Mycobacterium smegmatis co-expressed with siderophores mycobactin, exochelin and carboxymycobactin upon iron limitation. Methods Results smegmatis, grown presence of 0·02 μg Fe ml−1 (low iron) produced high levels all three siderophores, which were repressed bacteria supplemented 8 (high iron). Exochelin, major extracellular siderophore was first to rise expressed at during log phase growth. Carboxymycobactin, a minor...