title: bis-Molybdopterin guanine dinucleotide is required for persistence of Mycobacterium tuberculosis in guinea pigs.
abstract: Mycobacterium tuberculosis is able to synthesize molybdopterin cofactor (MoCo), which is utilized by numerous enzymes that catalyze redox reactions in carbon, nitrogen, and sulfur metabolism. In bacteria, MoCo is further modified through the activity of a guanylyltransferase, MobA, which converts MoCo to bis-molybdopterin guanine dinucleotide (bis-MGD), a form of the cofactor that is required by the dimethylsulfoxide (DMSO) reductase family of enzymes, which includes the nitrate reductase NarGHI. In this study, the functionality of the mobA homolog in M. tuberculosis was confirmed by demonstrating the loss of assimilatory and respiratory nitrate reductase activity in a mobA deletion mutant. This mutant displayed no survival defects in human monocytes or mouse lungs but failed to persist in the lungs of guinea pigs. These results implicate one or more bis-MGD-dependent enzymes in the persistence of M. tuberculosis in guinea pig lungs and underscore the applicability of this animal model for assessing the role of molybdoenzymes in this pathogen.
authors.affiliation: MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease & Molecular Medicine and Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa.
authors.forename: Monique J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Shanley
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zilavy
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Blas
authors.initials: B
authors.lastname: Peixoto
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease & Molecular Medicine and Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa.
authors.forename: Valerie
authors.initials: V
authors.lastname: Mizrahi
authors.affiliation: DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, University of the Witwatersrand, National Health Laboratory Service, Johannesburg, South Africa bavesh.kana@nhls.ac.za.
authors.forename: Bavesh D
authors.initials: BD
authors.lastname: Kana
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D006150:Guanine Nucleotides / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D050901:Nitrate Reductase / Q000235:genetics; D011622:Pterins / Q000378:metabolism*; D013466:Sulfurtransferases / Q000235:genetics; D014376:Tuberculosis / Q000382:microbiology*
chemical_list: D006150:Guanine Nucleotides; D011622:Pterins; C063761:molybdopterin guanine dinucleotide; D050901:Nitrate Reductase; D013466:Sulfurtransferases; C085585:molybdopterin synthase