title: Rv1894c is a novel hypoxia-induced nitronate monooxygenase required for Mycobacterium tuberculosis virulence.
abstract: Tuberculosis is difficult to cure, requiring a minimum of 6 months of treatment with multiple antibiotics. Small numbers of organisms are able to tolerate the antibiotics and persist in the lungs of infected humans, but they still require some metabolic activity to survive. We studied the role of the hypoxia-induced Rv1894c gene in Mycobacterium tuberculosis virulence in guinea pigs, which develop hypoxic, necrotic granulomas histologically resembling those in humans and found this gene to be necessary for full bacillary growth and survival. We characterized the function of the encoded enzyme as a nitronate monooxygenase, which is needed to prevent the buildup of toxic products during hypoxic metabolism and is negatively regulated by the transcriptional repressor KstR. Future studies will focus on developing small-molecule inhibitors that target Rv1894c and its homologs, with the goal of killing persistent bacteria, thereby shortening the time needed to treat tuberculosis.
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-0001, USA. klink@jhmi.edu
authors: Lee G
authors: LG
authors: Klinkenberg
authors: Petros C
authors: PC
authors: Karakousis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D023381:Endpoint Determination; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D005838:Genotype; D006168:Guinea Pigs; D000860:Hypoxia / Q000382:microbiology*; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D006899:Mixed Function Oxygenases