Biology subjects

Krishna, N.

Publications and source records attributed to Krishna, N..

4 recordsLinked to original sources

bioRxiv2026

Structure-Based Drug Design of Novel Inhibitors Targeting the Thiamine Biosynthesis Pathway in Bacteria

Current generation antibiotics are limited by poor target selectivity and are often mismanaged, leading to widespread antimicrobial resistance. The bacterial thiamine biosynthesis pathway offers compelling alternative since it is highly essential for bacterial survival and yet absent in humans. Genetic perturbations within pathway lead to documented auxotrophy and virulence defects, indicating low mutational tolerance within this pathway. Thiamine phosphate synthase is a key bottleneck enzyme performing the crucial role of coupling thiazole and pyrimidine moieties to form thiamine monophosphate. To develop a suitable inhibitor against it, a structure-based drug design pipeline was implemented. High-throughput virtual screening of nearly 1.5 million molecules provided sufficient exploration of chemical space. Further, R-group substitution was utilized for lead optimization. Structure-Activity Relationship analysis upon molecular mutants reveals patterns among R-group interactions to catalytic residues across various scaffolds. Additionally, ADMET screening and validation using molecular dynamics simulations resulted in a potent orally bioavailable broad-spectrum bactericidal molecule.

bioinformatics↗

bioRxiv2025

PATZ1 remodels the nucleosome landscape to promote chromatin accessibility in injured neurons

Adult central nervous system neurons fail to regenerate after injury, in part due to epigenetic constraints that maintain a growth-restrictive chromatin state. We previously showed that the transcription factor PATZ1 reprograms chromatin accessibility in injured corticospinal neurons to promote axon regeneration, but the underlying mechanism remained unclear. Here we use nucleosome-resolution profiling to reveal that PATZ1 induces widespread nucleosome eviction at regeneration-associated gene loci. PATZ1 treatment dramatically reduces both nucleosome occupancy and fuzziness, indicating active chromatin remodeling rather than passive destabilization. This remodeling occurs preferentially at distal regulatory elements, where PATZ1 drives a greater than 3-fold expansion of H3K27ac-marked active enhancers. Nucleosome eviction at these sites precedes enhancer activation, establishing a mechanistic link between chromatin remodeling and transcriptional reprogramming. Our findings demonstrate that targeted nucleosome eviction at enhancers underlies PATZ1-mediated chromatin reorganization, providing mechanistic insight into how epigenetic barriers to CNS regeneration can be overcome.

neuroscience↗

bioRxiv2022

Towards universal synthetic heterotrophy using a metabolic coordinator

Engineering the utilization of non-native substrates, or synthetic heterotrophy, in proven industrial microbes such as Saccharomyces cerevisiae represents an opportunity to valorize plentiful and renewable sources of carbon and energy as potential inputs to biotechnological processes. We previously demonstrated that activation of the galactose (GAL) regulon, a regulatory structure used by this yeast to coordinate substrate utilization with biomass formation during growth on galactose, during growth on the non-native substrate xylose results in a vastly altered gene expression profile and faster growth compared with constitutive overexpression of the same heterologous catabolic pathway. However, this effort involved the creation of a xylose-inducible variant of Gal3p (Gal3pS25144.1), the sensor protein of the GAL regulon, preventing this semi-synthetic regulon approach from being easily adapted to additional non-native substrates. Here, we report the construction of a variant Gal3pMC (metabolic coordinator) that exhibits robust GAL regulon activation in the presence of structurally diverse substrates and recapitulates the dynamics of the native system. Multiple molecular modeling studies confirm that Gal3pMC occupies conformational states corresponding to galactose-bound Gal3p in an inducer-independent manner. Using Gal3pMC to test a regulon approach to the assimilation of the non-native lignocellulosic sugars xylose, arabinose, and cellobiose yields higher growth rates and final cell densities when compared with a constitutive overexpression of the same set of catabolic genes. The subsequent demonstration of rapid and complete co-utilization of all three non-native substrates suggests that Gal3pMC-mediated dynamic global gene expression changes by GAL regulon activation may be universally beneficial for engineering synthetic heterotrophy.

synthetic biology↗

bioRxiv2021

Classifying Literature Extracted Events for Automated Model Extension

1In this study, we investigate the integration of three previously developed tools: FLUTE, VIOLIN, and CLARINET. We show how using these tools together adds additional capabilities in extending models from relevant research literature. We illustrate how we plan to address current modeling pitfalls with these tools (such as machine reading errors and literature volume), and how we plan to use these tools as the foundation for an automated model extension framework. Documentation and links to our tools can be found at: violin-tool.readthedocs.io clarinet-docs.readthedocs.io flute.readthedocs.io

systems biology↗