title: glpx Gene in Mycobacterium tuberculosis Is Required for In Vitro Gluconeogenic Growth and In Vivo Survival.
abstract: Several enzymes involved in central carbon metabolism and gluconeogenesis play a critical role in survival and pathogenesis of Mycobacterium tuberculosis (Mtb). The only known functional fructose 1,6-bisphosphatase (FBPase) in Mtb is encoded by the glpX gene and belongs to the Class II sub-family of FBPase. We describe herein the generation of a ΔglpX strain using homologous recombination. Although the growth profile of ΔglpX is comparable to that of wild type Mtb when grown on the standard enrichment media, its growth is dysgonic with individual gluconeogenic substrates such as oleic acid, glycerol and acetate. In mice lung CFU titers of ΔglpX were 2-3 log10 lower than the wild-type Mtb strain. The results indicate that glpX gene encodes a functional FBPase and is essential for both in vitro and in vivo growth and survival of Mtb. Loss of glpX results in significant reduction of FBPase activity but not complete abolition. These findings verify that the glpX encoded FBPase II in Mtb can be a potential target for drug discovery.
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Hiten J
authors.initials: HJ
authors.lastname: Gutka
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Movahedzadeh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002244:Carbon / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005798:Genes, Bacterial; D005943:Gluconeogenesis / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D009593:Nitroimidazoles / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects; D014376:Tuberculosis / Q000378:metabolism / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005227:Fatty Acids; D009593:Nitroimidazoles; C410767:pretomanid; D002244:Carbon; D006597:Fructose-Bisphosphatase