title: The role of the novel exopolyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence.
abstract: Inorganic polyphosphate (poly P) has been postulated to play a regulatory role in the transition to bacterial persistence. In bacteria, poly P balance in the cell is maintained by the hydrolysis activity of the exopolyphosphatase PPX. However, the Mycobacterium tuberculosis PPX has not been characterized previously. Here we show that recombinant MT0516 hydrolyzes poly P, and an MT0516-deficient M. tuberculosis mutant exhibits elevated intracellular levels of poly P and increased expression of the genes mprB, sigE, and rel relative to the isogenic wild-type strain, indicating poly P-mediated signaling. Deficiency of MT0516 resulted in decelerated growth during logarithmic-phase in axenic cultures, and tolerance to the cell wall-active drug isoniazid. The MT0516-deficient mutant showed a significant survival defect in activated human macrophages and reduced persistence in the lungs of guinea pigs. We conclude that exopolyphosphatase is required for long-term survival of M. tuberculosis in necrotic lung lesions.
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Seema M
authors: SM
authors: Thayil
authors: Norman
authors: N
authors: Morrison
authors: Norman
authors: N
authors: Schechter
authors: Harvey
authors: H
authors: Rubin
authors: Petros C
authors: PC
authors: Karakousis
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism*; D004251:DNA Transposable Elements / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005260:Female; D005816:Genetic Complementation Test; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007538:Isoniazid / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development / Q000472:pathogenicity; D011122:Polyphosphates / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D040681:Structural Homology, Protein; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D011122:Polyphosphates; D017766:Acid Anhydride Hydrolases; C020137:exopolyphosphatase; D007538:Isoniazid