GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogen Mycobacterium leprae

Abstract

Leprosy, caused by Mycobacterium leprae , has plagued humanity for thousands of years and continues to cause morbidity, disability and stigmatization in two to three million people today. Although effective treatment is available, the disease incidence has remained approximately constant for decades so new approaches, such as vaccine or new drugs, are urgently needed for control. Research is however hampered by the pathogen’s obligate intracellular lifestyle and the fact that it has never been grown in vitro . Consequently, despite the availability of its complete genome sequence, fundamental questions regarding the biology of the pathogen, such as its metabolism, remain largely unexplored. In order to explore the metabolism of the leprosy bacillus with a long-term aim of developing a medium to grow the pathogen in vitro , we reconstructed an in silico genome scale metabolic model of the bacillus, GSMN-ML. The model was used to explore the growth and biomass production capabilities of the pathogen with a range of nutrient sources, such as amino acids, glucose, glycerol and metabolic intermediates. We also used the model to analyze RNA-seq data from M . leprae grown in mouse foot pads, and performed Differential Producibility Analysis to identify metabolic pathways that appear to be active during intracellular growth of the pathogen, which included pathways for central carbon metabolism, co-factor, lipids, amino acids, nucleotides and cell wall synthesis. The GSMN-ML model is thereby a useful in silico tool that can be used to explore the metabolism of the leprosy bacillus, analyze functional genomic experimental data, generate predictions of nutrients required for growth of the bacillus in vitro and identify novel drug targets.

Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae

“…Gene essentiality in M. leprae is deciphered based on essentiality of homologous genes, mainly in M. tuberculosis that are determined by experiments (Sassetti et al, 2003;DeJesus et al, 2017). Because of the evolutionary loss of non-essential genes by pseudogenization, only 65% of the existing total of M. leprae genes have been demonstrated to be essentials (Borah et al, 2020). In order to identify potential drug targets, a chokepoint reaction analysis helps to find proteins that are either consumers of unique substrates, or are unique producers of metabolites.…”

Dissecting Host-Pathogen Interactions in TB Using Systems-Based Omic Approaches

“…developed a differential producibility analysis (DPA) algorithm to extract metabolite production profiles through integration of micro array gene expression data into GSMN-TB model ( 79 ). DPA using GSMN-ML, the first genome scale model of M. leprae , was applied to interrogate RNA-seq data to derive in vivo metabolite production of leprae bacillus and nutritional status ( 80 ). Metabolic variations within the Mtb complex were identified through comparisons of substrate utilisation rates, gene essentiality data and growth rates calculated from GSMN-TB, GSMN-MB ( M. bovis ) and GSMN-BCG ( M. bovis BCG) models ( 81 ).…”

Development of lipid biomarker based diagnostic method for TB research in archaeological samples via HPLC-HRMS

“…The Mycobacterium leprae is the causative agent of leprosy or Hansen's disease, however, the disease in less common cases are caused by its sister taxon, M. lepromatosis. M. leprae is an obligate intracellular human pathogen (Serrano-Coll et al, 2018;Blevins et al, 2020;Borah et al, 2020). In contrast with M. tuberculosis, M. leprae replicates mainly in Schwann cells and endothelial cells (Serrano- Coll et al, 2018;Borah et al, 2020).…”

“…M. leprae is an obligate intracellular human pathogen (Serrano-Coll et al, 2018;Blevins et al, 2020;Borah et al, 2020). In contrast with M. tuberculosis, M. leprae replicates mainly in Schwann cells and endothelial cells (Serrano- Coll et al, 2018;Borah et al, 2020). Leprosy can manifest as both disseminated infection and localized infection (Borah et al, 2020).…”

“…In contrast with M. tuberculosis, M. leprae replicates mainly in Schwann cells and endothelial cells (Serrano- Coll et al, 2018;Borah et al, 2020). Leprosy can manifest as both disseminated infection and localized infection (Borah et al, 2020). The characteristic disease caused by this infectious agent is damaging the skin and the peripheral nerve trunk (Serrano-Coll et al, 2018).…”