Publications by authors named "R Sowdhamini"

211 Publications

Antimicrobial Resistance Profiling and Phylogenetic Analysis of Clinical Isolates From Kenya in a Resource-Limited Setting.

Front Microbiol 2021 27;12:647565. Epub 2021 Jul 27.

National Centre for Biological Sciences, Tata Institute of Fundamental Research (TIFR), Bengaluru, India.

Background: Africa has one of the highest incidences of gonorrhea. is gaining resistance to most of the available antibiotics, compromising treatment across the world. Whole-genome sequencing (WGS) is an efficient way of predicting AMR determinants and their spread in the population. Recent advances in next-generation sequencing technologies like Oxford Nanopore Technology (ONT) have helped in the generation of longer reads of DNA in a shorter duration with lower cost. Increasing accuracy of base-calling algorithms, high throughput, error-correction strategies, and ease of using the mobile sequencer MinION in remote areas lead to its adoption for routine microbial genome sequencing. To investigate whether MinION-only sequencing is sufficient for WGS and downstream analysis in resource-limited settings, we sequenced the genomes of 14 suspected isolates from Nairobi, Kenya.

Methods: Using WGS, the isolates were confirmed to be cases of ( = 9), and there were three co-occurrences of with and ( = 2). has been implicated in sexually transmitted infections in recent years. The near-complete genomes ( = 10) were analyzed further for mutations/factors causing AMR using an in-house database of mutations curated from the literature.

Results: We observe that ciprofloxacin resistance is associated with multiple mutations in both gyrA and parC. Mutations conferring tetracycline () and sulfonamide () resistance and plasmids encoding beta-lactamase were seen in all the strains, and -containing plasmids were identified in nine strains. Phylogenetic analysis clustered the 10 isolates into clades containing previously sequenced genomes from Kenya and countries across the world. Based on homology modeling of AMR targets, we see that the mutations in GyrA and ParC disrupt the hydrogen bonding with quinolone drugs and mutations in FolP may affect interaction with the antibiotic.

Conclusion: Here, we demonstrate the utility of mobile DNA sequencing technology in producing a consensus genome for sequence typing and detection of genetic determinants of AMR. The workflow followed in the study, including AMR mutation dataset creation and the genome identification, assembly, and analysis, can be used for any clinical isolate. Further studies are required to determine the utility of real-time sequencing in outbreak investigations, diagnosis, and management of infections, especially in resource-limited settings.
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http://dx.doi.org/10.3389/fmicb.2021.647565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353456PMC
July 2021

DEELIG: A Deep Learning Approach to Predict Protein-Ligand Binding Affinity.

Bioinform Biol Insights 2021 7;15:11779322211030364. Epub 2021 Jul 7.

National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.

Protein-ligand binding prediction has extensive biological significance. Binding affinity helps in understanding the degree of protein-ligand interactions and is a useful measure in drug design. Protein-ligand docking using virtual screening and molecular dynamic simulations are required to predict the binding affinity of a ligand to its cognate receptor. Performing such analyses to cover the entire chemical space of small molecules requires intense computational power. Recent developments using deep learning have enabled us to make sense of massive amounts of complex data sets where the ability of the model to "learn" intrinsic patterns in a complex plane of data is the strength of the approach. Here, we have incorporated convolutional neural networks to find spatial relationships among data to help us predict affinity of binding of proteins in whole superfamilies toward a diverse set of ligands without the need of a docked pose or complex as user input. The models were trained and validated using a stringent methodology for feature extraction. Our model performs better in comparison to some existing methods used widely and is suitable for predictions on high-resolution protein crystal (⩽2.5 Å) and nonpeptide ligand as individual inputs. Our approach to network construction and training on protein-ligand data set prepared in-house has yielded significant insights. We have also tested DEELIG on few COVID-19 main protease-inhibitor complexes relevant to the current public health scenario. DEELIG-based predictions can be incorporated in existing databases including RSCB PDB, PDBMoad, and PDBbind in filling missing binding affinity data for protein-ligand complexes.
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http://dx.doi.org/10.1177/11779322211030364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274096PMC
July 2021

Disulfide-Rich Cyclic Peptides from Protect against β-Amyloid Toxicity and Oxidative Stress in Transgenic .

J Med Chem 2021 06 28;64(11):7422-7433. Epub 2021 May 28.

National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, Karnataka 560065, India.

Neurotoxic aggregation of β-amyloid (Aβ) peptides is a hallmark of Alzheimer's disease and increased reactive oxygen species (ROS) is an associated process. In the present study, we report the neuroprotective effects of disulfide-rich, circular peptides from () (butterfly pea) on Aβ-induced toxicity in transgenic . Cyclotides (∼30 amino acids long) are a special class of cyclic cysteine knot peptides. We show that cyclotide-rich fractions from different plant tissues delay Aβ-induced paralysis in the transgenic CL4176 strain expressing the human muscle-specific Aβ gene. They also improved Aβ-induced chemotaxis defects in CL2355 strain expressing Aβ in the neuronal cells. ROS assay suggests that this protection is likely mediated by the inhibition of Aβ oligomerization. Furthermore, Aβ deposits were reduced in the CL2006 strain treated with the fractions. The study shows that cyclotides from could be a source of a novel pharmacophore scaffold against neurodegenerative diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00033DOI Listing
June 2021

Genome-wide survey of tyrosine phosphatases in thirty mammalian genomes.

Cell Signal 2021 Aug 20;84:110009. Epub 2021 Apr 20.

National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, Karnataka, 560 065, India. Electronic address:

The age of genomics has given us a wealth of information and the tools to study whole genomes. This, in turn, has facilitated genome-wide studies among organisms that were relatively less studied in the pre-genomic era or are non-model organisms. This paves the way to the discovery of interesting evolutionary patterns, which are brought to light by genome-wide surveys of protein superfamilies. Phosphorylation is a post-translational modification that is utilised across all clades of life, and acts as an important signalling switch, regulating several cellular processes. Tyrosine phosphatases, which are found predominantly in eukaryotes, act on phosphorylated tyrosine residues and sometimes on other substrates. Extending on our previous effort to look for tyrosine phosphatases in the human genome, we have looked for sequences of the cysteine-based tyrosine phosphatase superfamily in thirty mammalian genomes from all across Mammalia and validated the sequences with the presence of the signature catalytic motif. Domain architecture annotation, followed by in-depth analysis, revealed interesting taxon-specific patterns such as subtle differences between the protein families in marsupials and early mammals versus placental mammals. Finally, we discuss an interesting case of loss of the tyrosine phosphatase domain from a gene product in the course of eutherian evolution.
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http://dx.doi.org/10.1016/j.cellsig.2021.110009DOI Listing
August 2021

Chronic exposure of humans to high level natural background radiation leads to robust expression of protective stress response proteins.

Sci Rep 2021 01 19;11(1):1777. Epub 2021 Jan 19.

Radiation Signaling Group, Bio-Science Group, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre (BARC), Mumbai, 400 085, India.

Understanding exposures to low doses of ionizing radiation are relevant since most environmental, diagnostic radiology and occupational exposures lie in this region. However, the molecular mechanisms that drive cellular responses at these doses, and the subsequent health outcomes, remain unclear. A local monazite-rich high level natural radiation area (HLNRA) in the state of Kerala on the south-west coast of Indian subcontinent show radiation doses extending from ≤ 1 to ≥ 45 mGy/y and thus, serve as a model resource to understand low dose mechanisms directly on healthy humans. We performed quantitative discovery proteomics based on multiplexed isobaric tags (iTRAQ) coupled with LC-MS/MS on human peripheral blood mononuclear cells from HLNRA individuals. Several proteins involved in diverse biological processes such as DNA repair, RNA processing, chromatin modifications and cytoskeletal organization showed distinct expression in HLNRA individuals, suggestive of both recovery and adaptation to low dose radiation. In protein-protein interaction (PPI) networks, YWHAZ (14-3-3ζ) emerged as the top-most hub protein that may direct phosphorylation driven pro-survival cellular processes against radiation stress. PPI networks also identified an integral role for the cytoskeletal protein ACTB, signaling protein PRKACA; and the molecular chaperone HSPA8. The data will allow better integration of radiation biology and epidemiology for risk assessment [Data are available via ProteomeXchange with identifier PXD022380].
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http://dx.doi.org/10.1038/s41598-020-80405-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815775PMC
January 2021
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