Biology subjects

Malhotra, S.

Publications and source records attributed to Malhotra, S..

22 records · Page 2Linked to original sources

bioRxiv2019

Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification

Translational frameshift errors are often deleterious to the synthesis of functional proteins as they lead to the production of truncated or inactive proteins. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and has been identified as a therapeutic target for several bacterial infections. Here we validate TrmD as a target in Mycobacterium abscessus and describe the application of a structure-guided fragment-based drug discovery approach for the design of a new class of inhibitors against this enzyme. A fragment library screening followed by structure-guided chemical elaboration of hits led to the development of compounds with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and Mycobacterium tuberculosis. The compounds were further active in macrophage infection models against Mycobacterium leprae and M. abscessus suggesting the potential for novel broad-spectrum mycobacterial drugs.

biochemistry↗

bioRxiv2019

Comparative analyses of metabolic pathways in mycobacteria: Insights into the identification and characterisation of new drug targets in M. tuberculosis, M. leprae and M. abscessus

Three related mycobacteria are the cause of widespread infections in man and are the focus of intense research and drug-discovery efforts in the face of growing antimicrobial resistance. Mycobacterium tuberculosis, the causative agent of tuberculosis, is currently one of the top ten causes of death in the world according to WHO; M. abscessus, a group of non-tuberculous mycobacteria causes lung infections and other opportunistic infections in humans; and M. leprae, the causative agent of leprosy, remains endemic in tropical countries. There is an urgent need to design alternatives to conventional treatment strategies, due to the increase in resistance to standard antibacterials. In this study, we present a comparative analysis of chokepoint and essentiality datasets that will provide insight into the development of new treatment regimes. We illustrate the key metabolic pathways shared between these three organisms and identify drug targets with a wide metabolic impact that are common to the three species. We demonstrate that 72% of the chokepoint enzymes are proteins essential to Mycobacterium tuberculosis. We show also that 78% of the drug targets, prioritized based on their presence in multiple paths on the metabolic network, are present in pathways shared by M. tuberculosis, M. leprae and M. abscessus, including biosynthesis of amino acids, carbohydrates, cell structures, fatty acid and lipid biosynthesis. A further 17% is found in the prioritised pathways shared between M. tuberculosis and M. abscessus. We have performed comparative structure modelling of potential drug targets identified using our analysis in order to assess druggability and demonstrate the importance of chokepoint analysis in terms of drug target identification. AUTHOR SUMMARYComputer simulation studies to design new drugs against mycobacteria

bioinformatics↗

bioRxiv2018

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma

Continual evolution of cancer makes it challenging to predict clinical outcomes. Highly varied and unpredictable patient outcomes in esophageal adenocarcinoma (EAC) prompted us to question the pattern and timing of metastatic spread. Whole genome sequencing and phylogenetic analysis of 396 samples across 18 EAC cases demonstrated a stellate pattern on the phylogenetic trees in 90% cases. The age-dependent trinucleotide signature, which can serve as a molecular clock, was absent or reduced in the stellate branches beyond the trunk in most cases (p<0.0001). Clustering of lymph nodes and distant metastases (n=250) demonstrated samples sharing a common clonal origin were widely dispersed anatomically. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time-points. We infer that metastasis occurs rapidly across multiple sites, constituting a model of metastatic spread we term clonal diaspora. This has implications for understanding metastatic progression, clinical staging and patient management.

genomics↗

bioRxiv2017

Lamellar Junctions In The Endolymphatic Sac Act As A Relief Valve To Regulate Inner Ear Pressure

The inner ear is a fluid-filled closed-epithelial structure whose normal function requires maintenance of an internal hydrostatic pressure and fluid composition by unknown mechanisms. The endolymphatic sac (ES) is a dead-end epithelial tube connected to the inner ear. ES defects can cause distended ear tissue, a pathology often seen in hearing and balance disorders. Using live imaging of zebrafish larvae, we reveal that the ES undergoes cycles of slow pressure-driven inflation followed by rapid deflation every 1-3 hours. Using serial-section electron microscopy and adaptive optics lattice light-sheet microscopy, we find a pressure relief valve in the ES comprised of thin overlapping basal lamellae that dynamically extend over neighboring cells before rupturing under pressure leading to ES collapse. The unexpected discovery of a physical relief valve in the ear emphasizes the need for further study into how organs control fluid pressure, volume, flow, and ion homeostasis in development and disease.

developmental biology↗