title: In vitro and in vivo studies of a rapid and selective breath test for tuberculosis based upon mycobacterial CO dehydrogenase.
abstract: One of the major hurdles in treating tuberculosis (TB) is the time-consuming and difficult methodology for diagnosis. Stable-isotope breath tests hold great potential for rapidly diagnosing an infectious disease, monitoring therapy, and determining a bacterial phenotype in a rapid, point-of-care manner that does not require invasive sampling. Here we describe the preclinical development of a potentially highly selective TB diagnostic breath test based upon the organism's CO dehydrogenase activity. After development of the test in vitro, we were able to use the breath test to discriminate between infected and control rabbits, demonstrating that a diagnosis can potentially be made and also that a complex bacterial phenotype can be noninvasively and rapidly studied in the host. IMPORTANCE Tuberculosis (TB) remains a major infectious cause of disease and death worldwide, and effective diagnosis and then treatment are the tools with which we fight TB. The more quickly and more specific the diagnosis can be made, the better, and this is also true of diagnosis being as close to the patient (point of care) as possible. Here we report our preclinical development of breath tests based upon specific mycobacterial metabolism that could, with development, allow rapid point-of-care diagnosis through measuring the mycobacterial conversion of labeled CO to labeled CO2.
authors.forename: Mamoudou
authors.initials: M
authors.lastname: Maiga
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Choi
authors.forename: Viorel
authors.initials: V
authors.lastname: Atudorei
authors.forename: Mariama C
authors.initials: MC
authors.lastname: Maiga
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Sharp
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.forename: Graham S
authors.initials: GS
authors.lastname: Timmins
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001944:Breath Tests / Q000379:methods; D004195:Disease Models, Animal; D009097:Multienzyme Complexes / Q000378:metabolism*; D009161:Mycobacterium / Q000201:enzymology*; D019095:Point-of-Care Systems; D011817:Rabbits; D014376:Tuberculosis / Q000175:diagnosis*
chemical_list: D009097:Multienzyme Complexes; D000445:Aldehyde Oxidoreductases; C019823:carbon monoxide dehydrogenase
references.citation: BMC Public Health. 2008 Jan 14;8:15
references.pmid: 18194573
references.citation: Annu Rev Pharmacol. 1975;15:409-23
references.pmid: 1096793
references.citation: Lab Invest. 2012 Nov;92(11):1541-52
references.pmid: 22964851
references.citation: Infect Immun. 2013 Jul;81(7):2536-45
references.pmid: 23630967
references.citation: Am J Gastroenterol. 1996 Feb;91(2):233-8
references.pmid: 8607486
references.citation: Zh Mikrobiol Epidemiol Immunobiol. 1985 Feb;(2):11-4
references.pmid: 3922179
references.citation: ACS Chem Biol. 2012 Jan 20;7(1):166-71
references.pmid: 22007661
references.citation: PLoS One. 2010 Aug 27;5(8):e12451
references.pmid: 20805989
references.citation: Lancet. 1987 May 23;1(8543):1174-7
references.pmid: 2883491
references.citation: PLoS One. 2013 May 06;8(5):e62618
references.pmid: 23671613
references.citation: Cell Host Microbe. 2008 May 15;3(5):323-30
references.pmid: 18474359
references.citation: Arch Toxicol. 1980 Feb;43(4):273-81
references.pmid: 7387387
references.citation: Indian J Med Res. 2007 Sep;126(3):193-8
references.pmid: 18037712
references.citation: J Biol Chem. 1977 Jun 10;252(11):3881-90
references.pmid: 405387
references.citation: Appl Environ Microbiol. 1979 May;37(5):932-7
references.pmid: 485139
references.citation: Genes Dev. 2007 Mar 1;21(5):601-14
references.pmid: 17344419
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1980 Oct;49(4):589-600
references.pmid: 6777345
references.citation: J Biol Chem. 2008 Jun 27;283(26):18032-9
references.pmid: 18400743
references.citation: J Med Chem. 2009 Jul 9;52(13):4063-7
references.pmid: 19438226
references.citation: Thorax. 1986 Nov;41(11):886-7
references.pmid: 3824275
references.citation: Anal Chem. 2008 Jul 1;80(13):4820-4
references.pmid: 18533685
references.citation: Indian J Med Microbiol. 2007 Oct;25(4):336-45
references.pmid: 18087081
references.citation: Lancet Infect Dis. 2009 Mar;9(3):162-72
references.pmid: 19246020
references.citation: Appl Environ Microbiol. 2003 Dec;69(12):7266-72
references.pmid: 14660375
references.citation: Infect Immun. 2009 Feb;77(2):598-603
references.pmid: 19064634
references.citation: J Med Microbiol. 2008 Jul;57(Pt 7):814-819
references.pmid: 18566138
references.citation: Acta Physiol Scand. 1990 Apr;138(4):471-8
references.pmid: 2112822
references.citation: Infect Immun. 1996 Nov;64(11):4776-87
references.pmid: 8890239
references.citation: J Bacteriol. 2003 Jan;185(1):142-7
references.pmid: 12486050
references.citation: Curr Pharm Des. 2010;16(29):3300-9
references.pmid: 20819064
references.citation: J Infect. 2008 Aug;57(2):103-9
references.pmid: 18649943
references.citation: J Clin Microbiol. 1982 May;15(5):976-8
references.pmid: 7047563
references.citation: Lancet Infect Dis. 2007 Jul;7(7):481-90
references.pmid: 17524807
references.citation: J Infect Dis. 2012 May 15;205 Suppl 2:S250-7
references.pmid: 22448027
references.citation: Clin Rev Allergy Immunol. 2009 Dec;37(3):159-66
references.pmid: 19330553
references.citation: Toxicology. 2000 Apr 7;145(1):1-14
references.pmid: 10771127