02524nas a2200289   4500000000100000008004100001260001200042100001200054700001400066700001500080700001100095700000900106700001300115700001700128700001200145700001200157700001000169700001300179700001500192700001500207245011400222856009900336300001300435490000700448520176500455022001402220       2020                            d  c07/20201 aBorah K1 aKearney J1 aBanerjee R1 aVats P1 aWu H1 aDahale S1 aKasibhatla S1 aJoshi R1 aBonde B1 aOjo O1 aLahiri R1 aWilliams D1 aMcFadden J00aGSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogen Mycobacterium leprae.  uhttps://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0007871&type=printable  ae00078710 v143 a<p>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.</p>  a1935-2735