Biotin biosynthesis in Mycobacterium tuberculosis: physiology, biochemistry and molecular intervention

Salaemae, Wanisa; Azhar, Al; Booker, Grant W.; Polyak, Steven W.

doi:10.1007/s13238-011-1100-8

Cited by 59 publications

(63 citation statements)

References 42 publications

(47 reference statements)

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“…Biotin has been reported as being required for Mycobacterium tuberculosis virulence in mice and Vibrio cholera colonization of the mouse intestine, both through unknown mechanisms (26)(27)(28). In addition, several antimicrobials target the biotin pathway by causing the degradation of biotin or biotin precursors including amiclenomycin, actithiazic acid, and the biotin analog α-dehydrobiotin (29-31), further demonstrating the importance of biotin during infection, as well as the therapeutic utility of limiting biotin availability to pathogens.…”

Section: Discussionmentioning

confidence: 99%

Link between intraphagosomal biotin and rapid phagosomal escape in Francisella

Napier

Meyer

Bina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cytosolic bacterial pathogens require extensive metabolic adaptations within the host to replicate intracellularly and cause disease. In phagocytic cells such as macrophages, these pathogens must respond rapidly to nutrient limitation within the harsh environment of the phagosome. Many cytosolic pathogens escape the phagosome quickly (15-60 min) and thereby subvert this host defense, reaching the cytosol where they can replicate. Although a great deal of research has focused on strategies used by bacteria to resist antimicrobial phagosomal defenses and transiently pass through this compartment, the metabolic requirements of bacteria in the phagosome are largely uncharacterized. We previously identified a Francisella protein, FTN_0818, as being essential for intracellular replication and involved in virulence in vivo. We now show that FTN_0818 is involved in biotin biosynthesis and required for rapid escape from the Francisella-containing phagosome (FCP). Addition of biotin complemented the phagosomal escape defect of the FTN_0818 mutant, demonstrating that biotin is critical for promoting rapid escape during the short time that the bacteria are in the phagosome. Biotin also rescued the attenuation of the FTN_0818 mutant during infection in vitro and in vivo, highlighting the importance of this process. The key role of biotin in phagosomal escape implies biotin may be a limiting factor during infection. We demonstrate that a bacterial metabolite is required for phagosomal escape of an intracellular pathogen, providing insight into the link between bacterial metabolism and virulence, likely serving as a paradigm for other cytosolic pathogens. S ubversion of the hostile phagosomal environment is required for the survival of intracellular bacteria. Although bacterial strategies to resist antimicrobial phagosomal defenses have been studied in great detail (1, 2), the ways in which bacteria counter phagosomal nutrient limitation are largely unknown. This is especially true for cytosolic pathogens that are often in the phagosome for a very limited time (15-60 min), before escaping this compartment to reach their replicative niche in the cytoplasm. During this brief and dynamic time, it is unclear if cytosolic pathogens require sequestration of nutrients or synthesis of de novo metabolites to promote their virulence strategies and escape the toxic phagosome.Francisella tularensis is a cytosolic intracellular Gram-negative bacterial pathogen that uses a multitude of mechanisms to evade phagosomal host defenses (3). This pathogen is highly virulent and causes the potentially fatal disease tularemia. Francisella novicida U112 and Francisella holarctica LVS (live vaccine strain) are less virulent yet highly related strains that are often used as models to study F. tularensis. Like other cytosolic bacterial pathogens, after initial contact with the host macrophage, Francisella spp. are taken up into a phagosome and rapidly escape (30-60 min) this compartment to reach and replicate within the cytosol (3-5). The mechanism by w...

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Section: Discussionmentioning

confidence: 99%

Link between intraphagosomal biotin and rapid phagosomal escape in Francisella

Napier

Meyer

Bina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In bacteria, biotin serves as an essential cofactor for biotin-dependent enzymes, namely pyruvate carboxylase (PC) to replenish the Krebs cycle and acyl-CoA carboxylase (ACC) for membrane biogenesis and maintenance [2], [3], [4] and [5]. As the cell membrane provides a defensive barrier against environmental toxins, host immune factors and antibiotic agents [6] and [7], the metabolic pathways related to the synthesis of membrane lipids have been suggested as promising targets for the development of new antibiotics.…”

Section: Introductionmentioning

confidence: 99%

“…As the cell membrane provides a defensive barrier against environmental toxins, host immune factors and antibiotic agents [6] and [7], the metabolic pathways related to the synthesis of membrane lipids have been suggested as promising targets for the development of new antibiotics. Genetic studies have revealed important roles for biotin biosynthesis in Mycobacterium tuberculosis during growth, infection and the latency phase, thus establishing this pathway as a potential drug target for new anti-tuberculosis therapies [3], [8], [9], [10], [11] and [12]. In addition, biotin biosynthesis has been intensively studied in other bacteria and the enzymes involved in the pathway have been implicated in bacterial virulence during infection and intracellular replication [13].…”

Section: Introductionmentioning

confidence: 99%

Nucleotide triphosphate promiscuity in Mycobacterium tuberculosis dethiobiotin synthetase

et al. 2015

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In all cases accepted manuscripts should:  link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article Embargo 1472-9792Tuberculosis 12months Here we provide evidence to show that MtDTBS has a broad nucleotide specificity due to the absence of the gate-keeper residue.

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“…Biotin is the essential cofactor of biotin-dependent carboxylases such as pyruvate carboxylase and acetyl-CoA carboxylase (60); therefore, it is necessary for cell growth, the production of fatty acids, and the metabolism of amino acids. Additionally, recent reports have revealed that biotin synthesis is essential for bacterial growth, infection, and survival during the latent phase of Mycobacterium marinum (61,62). In this study, the mutants inactivated in biotin synthesis-related genes were attenuated Ͼ700,000-to 2,000,000-fold compared with wild-type strain Yb2, demonstrating that biotin synthesis plays an important role in the pathogenicity of R. anatipestifer.…”

Section: Discussionmentioning

confidence: 50%

Whole-Genome Sequence Analysis and Genome-Wide Virulence Gene Identification of Riemerella anatipestifer Strain Yb2

Wang

Ding

Wang

et al. 2015

Appl Environ Microbiol

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Riemerella anatipestifer is a well-described pathogen of waterfowl and other avian species that can cause septicemic and exudative diseases. In this study, we sequenced the complete genome of R. anatipestifer strain Yb2 and analyzed it against the published genomic sequences of R. anatipestifer strains DSM15868, RA-GD, RA-CH-1, and RA-CH-2. The Yb2 genome contains one circular chromosome of 2,184,066 bp with a 35.73% GC content and no plasmid. The genome has 2,021 open reading frames that occupy 90.88% of the genome. A comparative genomic analysis revealed that genome organization is highly conserved among R. anatipestifer strains, except for four inversions of a sequence segment in Yb2. A phylogenetic analysis found that the closest neighbor of Yb2 is RA-GD. Furthermore, we constructed a library of 3,175 mutants by random transposon mutagenesis, and 100 mutants exhibiting more than 100-fold-attenuated virulence were obtained by animal screening experiments. Southern blot analysis and genetic characterization of the mutants led to the identification of 49 virulence genes. Of these, 25 encode cytoplasmic proteins, 6 encode cytoplasmic membrane proteins, 4 encode outer membrane proteins, and the subcellular localization of the remaining 14 gene products is unknown. The functional classification of orthologous-group clusters revealed that 16 genes are associated with metabolism, 6 are associated with cellular processing and signaling, and 4 are associated with information storage and processing. The functions of the other 23 genes are poorly characterized or unknown. This genome-wide study identified genes important to the virulence of R. anatipestifer. Riemerella anatipestifer is a Gram-negative, non-spore-forming, nonmotile, capsule-like, rod-shaped bacterium. It is reported worldwide as the cause of epizootic infectious polyserositis in domestic ducks (1); it is also pathogenic for geese, turkeys, chickens, and other birds (2, 3). R. anatipestifer infection occurs in acute form in ducks less than about 8 weeks of age and in chronic form in older birds. It causes major economic losses in the duck industry by causing a high mortality rate, poor feed conversion, increased condemnations, and high treatment costs (4, 5).Currently, 21 serotypes of R. anatipestifer have been identified by slide and tube agglutination tests using antisera (6). There is a large variation in virulence between different serotypes and strains, as assessed by mortality and morbidity rates (7). Infections with R. anatipestifer serotypes 1, 2, 3,5,6,7,8,10,11,13,14, and 15 have been reported in China, with serotypes 1, 2, and 10 being responsible for most of the major outbreaks (8). There is very little knowledge about the molecular bases of R. anatipestifer virulence, except for the virulence factors VapD, the Christie-AtkinsMunch-Peterson (CAMP) cohemolysin, and OmpA. VapD shows homology to virulence-associated proteins in other bacteria (9). The CAMP cohemolysin is a sialoglycoprotease produced during natural infection under certain intrace...

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Biotin biosynthesis in Mycobacterium tuberculosis: physiology, biochemistry and molecular intervention

Cited by 59 publications

References 42 publications

Link between intraphagosomal biotin and rapid phagosomal escape in Francisella

Link between intraphagosomal biotin and rapid phagosomal escape in Francisella

Nucleotide triphosphate promiscuity in Mycobacterium tuberculosis dethiobiotin synthetase

Whole-Genome Sequence Analysis and Genome-Wide Virulence Gene Identification of Riemerella anatipestifer Strain Yb2

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