Disease relevance of Mycobactin

• Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall [1].
• Overproduction and purification of the mbtB ArCP domain and MbtA in Escherichia coli allowed validation of the mycobactin initiation hypothesis, as sequential action of PptT (a phosphopantetheinyl transferase) and MbtA (a salicyl-AMP ligase) resulted in the mbtB ArCP domain being activated as salicyl-S-ArCP [2].
• The exochelins are proposed as the functional extracellular iron-binding agents of BCG and other mycobacteria, the role of mycobactin being confined to that of a cell wall iron transporter [3].
• These data indicate that 7H12 radiometric broth was able to rapidly demonstrate the mycobactin dependence of M. paratuberculosis and GLC and TLC procedures were capable of rapidly differentiating this organism from the other mycobacteria studied [4].
• Rhodococcus bronchialis, R. terrae and R. rubropertinctus formed mycobactins, whereas the remaining species (R. coprophilus, R. equi, R. erythropolis, R. rhodnii, R. rhodochrous, R. ruber, R. maris and R. luteus) failed to synthesize these compounds even under conditions of strictly iron-limited growth [5].

High impact information on Mycobactin

• The finding that ferri-exochelins but not iron transferrin transfer iron to mycobactins in the cell wall underscores the importance of exochelins in iron acquisition [1].
• These molecules share a common core structure with another type of high-affinity iron-binding molecule located in the cell wall of M. tuberculosis: the mycobactins [1].
• The Rv1347c protein does not show this activity, however, and we show from its crystal structure, coupled with functional and bioinformatic data, that its most likely role is in the biosynthesis of mycobactin, the M. tuberculosis siderophore [6].
• Modeling the postulated substrate, the N(epsilon)-hydroxylysine side chain of mycobactin, into the acceptor substrate binding groove identifies two residues at the active site, His130 and Asp168, that have putative roles in substrate binding and catalysis [6].
• Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin [2].

Chemical compound and disease context of Mycobactin

• Mycobacterium tuberculosis mycobactins are mixed polyketide/nonribosomal peptides that contain a hydroxyaryloxazoline cap and two N-hydroxyamides that together create a high-affinity site for ferric ion [2].
• Evaluation of growth promotion and inhibition from mycobactins and nonmycobacterial siderophores (Desferrioxamine and FR160) in Mycobacterium aurum [7].
• Heterologous mycobactins and the synthetic FR160 [N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (C3 0H4 6N3, O6 Br)] promoted growth in Mycobacterium aurum in low concentrations [7].
• The structure of MbtI from Mycobacterium tuberculosis, the first enzyme in the biosynthesis of the siderophore mycobactin, reveals it to be a salicylate synthase [8].
• Mycobacterium tuberculosis acquires iron exclusively via the siderophore mycobactin T, the biosynthesis of which depends on the production of salicylate from chorismate [8].

Biological context of Mycobactin

• RESULTS: A ten-gene cluster spanning 24 kilobases of the M. tuberculosis genome, designated mbtA-J, contains the core components necessary for mycobactin biogenesis [2].
• One mutant with a block in mycobactin biosynthesis was generated from strain mc(2)155 by chemical mutagenesis [9].
• Nucleic acid hybridization studies of mycobactin-dependent mycobacteria [10].
• Genes predicted to encode metabolic pathways were overrepresented in the LSPs, and analysis revealed a polymorphism within the mycobactin biosynthesis operon that potentially explains the in vitro mycobactin dependence of M. avium subsp. paratuberculosis [11].
• The transposon insertion sites were identified, and sequence analyses of the cloned flanking chromosome regions showed that the mutated gene in LUN9 was an orthologue of the Mycobacterium tuberculosis mycobactin biosynthetic gene mbtE [12].

Anatomical context of Mycobactin

• Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ [13].
• The mean Z value (degrees required for the decimal reduction time to traverse one log cycle) was 8.6 degrees C. These five strains showed similar survival whether recovery was on Herrold's egg yolk medium containing mycobactin or by a radiometric culture method (BACTEC) [14].
• In our experiments, these mycobactin-targeted lipid droplets were found in direct contact with phagosomes, poised for iron delivery [15].
• Although M. paratuberculosis was not recovered from inoculated rabbits when fecal cultures were incubated three months in vitro, a slow-growing mycobactin-dependent form of Mycobacterium was recovered from feces and ileal tissue after incubation for 11-15 months [16].

Associations of Mycobactin with other chemical compounds

• The mycobactin gene cluster has organizational homologies to the yersiniabactin and enterobactin synthetase genes [2].
• A commercial radiometric medium, BACTEC 12B, was modified by addition of mycobactin, egg yolk suspension, and antibiotics (vancomycin, amphotericin B, and nalidixic acid) [17].
• For culture, three different culture media (modified Herrold egg yolk with mycobactin; Lowenstein-Jensen [L-J]; and L-J with cyclohexamide, naladixic acid, and lincomycin) were tested to determine which medium had the greatest success in isolating mycobacteria [18].
• The protein MbtI is thought to be the isochorismate synthase enzyme responsible for the conversion of chorismate to isochorismate, the first step in the salicylate production required for mycobactin biosynthesis [19].

Gene context of Mycobactin

• In addition, evidence is presented that suggests iron-containing transferrin and lactoferrin at low pH may circumvent the need for mycobactin by M. paratuberculosis [20].
• The mutated gene in LUN8 had homology with M. tuberculosis fadD33 (Rv1345), a gene that may encode an acyl-coenzyme A synthase and which previously was not known to participate in synthesis of mycobactin [12].
• Since M. leprae cells contain cytochrome c and since mycobactin is essential to growth of all mycobacteria, M. leprae might be considered as a microbe dependent microbe [21].
• Mycobacterium leprae iron nutrition: bacterioferritin, mycobactin, exochelin and intracellular growth [22].

Analytical, diagnostic and therapeutic context of Mycobactin

• The separation of the mycobactins from Mycobacterium smegmatis by using high-pressure liquid chromatography [23].
• The method developed here allows sensitive detection of mycobactin by thin-layer chromatography from as little as 5 ml of culture after a 2-week incubation [24].
• Cultures were performed by using radiometric culture and acid-fast isolates were identified by 16S/IS900/IS1311 PCR and mycobactin dependency characteristics [25].
• Other iron-binding compounds, including purified siderophores from unrelated organisms and host iron-binding proteins were also evaluated in the bioassay for growth induction of M. paratuberculosis in the absence of mycobactin [20].
• Antigenic analysis by immunodiffusion has been applied to 74 strains of mycobactin-dependent mycobacteria [26].

References