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I am Kumar Sachin Singh did my PhD in 2017 from JNU Delhi and CSIR-Central Drug Research Institute; Lucknow (India) titled “Characterization of selected genes of glycine metabolic pathway and their role in mycobacterial survival” under the supervision of Dr. Sudheer Kumar Singh. Currently, I am working in Mitreva lab in Washington University In St. Louis. I am involved in various projects but basically I am assigned for DARPA project (equivalent to DRDO in India). In Mitreva lab, I am working on various nematodes to make them a beneficial commensal to make a biological PPE to counter biological and chemical warfare for military. It involves the whole genomic study of nematodes, Biochemistry, genetic modifications using CRISPR Cas9 and proteomics, animal study and toxicity.
After Ph.D in 2017 I had joined post doc in June 2017 in Dotiwala lab in Wistar Institute, Philadelphia. As a Postdoc in Farokh Dotiwala lab, I had worked on the antimicrobials against the pathogen specific isoprenoid biosynthetic pathway called MEP pathway. These antibiotics are not only a potent inhibitors but have the tendency to activate strong immune responses against the pathogen in the host.
I had also worked on the TP53 variant at amino acid 47 in humans predominantly in African descent individuals. This variant shows increased cancer risk due to defective ferroptosis. We had discovered that this defect leads to the accumulation of iron in the macrophages that alters cytokine profile and various other pathways leads to increased intracellular bacterial pathogenesis but shows protective action against the malaria toxin hemozoin. This study will be a stepping stone in the field of personalized medicine to address health disparities arising from such SNP (Singh et. al., Nat. Commun. 2020).
During my PhD, I worked on a complex network of glycine metabolic pathway of Mycobacterium tuberculosis for the identification of possible drug targets. The glycine being an important component of protein synthesis, one carbon metabolism, serine biosynthesis, nucleotide biosynthesis, methylation processes and for redox balancing (as glutathione in other systems). We had decided to explore various approaches of glycine biosynthesis in Mycobacterium tuberculosis. The glycine being structurally simpler is neither a D- nor L-amino acid and can act as a substrate for D-amino acid oxidase (DAO). DAO is a FAD dependent enzyme catalysing the glycine to glyoxylate conversion in the presence of oxygen. Ammonia and hydrogen peroxide are by-products of reaction. We had found that D-amino acid oxidase is important for the growth of mycobacteria and in carbon assimilation under in vitro conditions and pathway stimulation in presence of specified media conditions; we had also observed the differential expression of D-amino acid oxidase under aerobic and hypoxic stress condition, we had also shown the localization D-amino acid oxidase in the cellular fractions. D-amino acid oxidase causes growth attenuation upon infection in the mouse and is not able to establish the Mtb infection. We had observed that apart from DAO importance in the survival in mice it also played an important role in antibiotic sensitivity, efflux-influx, biofilm formation and ability to persistence. We had also found that the knockout strain was not able escape from the phagosomal maturation process in bone derived mouse macrophage while the WT and Complemented strain resist phagosomal maturation. To trace the phagosomal maturation we had identified and observed the expression of EEA1, Rab5, Cathepsin D, LAMP1 and iNOS (in mouse) while phagosomal acidification (using Lysotracker) through fluorescence based confocal microscopy and image analysis along with WT and Knockout complemented strains (Singh et al., 2015, 2017, 2021). Apart from this we had also done the in vivo experimentation in mice (BalB/C) model to observe the effect of deletion of DAO of Mtb in mice post infection by performing the cfu, cytokine profiling and histopathology. Apart from this I had also work on glycine cleavage system, glycine is used for both protein synthesis, purine biosynthesis and one carbon units derived from glycine cleavage are required for the biosynthesis of methionine, thymine, purines and numerous other methylated products. Serine hydroxymethyltransferase and S-aminomethyltransferase of glycine cleavage system of mycobacteria was found very promising for redox balancing of bacterial cells under antibiotic stress for drug target perspective.
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Papers共 12 篇Author StatisticsCo-AuthorSimilar Experts
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Tuberculosis (Edinburgh, Scotland) (2021): 102079-102079
Natureno. 7885 (2021): 518-518
Natureno. 7843 (2020): 597-602
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