Review: Multidrug‐resistant tuberculosis: public health challenges

Coker, Richard

doi:10.1046/j.1365-3156.2003.01156.x

Cited by 122 publications

(62 citation statements)

References 55 publications

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“…To determine the optimal length of oligomannopyranosides for ManT catalysis, oligosaccharides 4-7 were screened as potential substrates for the enzyme in a cell-free assay by using 3 Hlabeled GDP-mannose (2, Scheme 2), which is converted to PPM (3, Scheme 2), by the membrane fraction. [31] The results are summarized in Table 1.…”

Section: Optimal Length Of Oligomannopyranosides For Mant a C H T U Nmentioning

confidence: 99%

“…[1][2][3] TB has been the subject of increasing recent concern due not only to difficulties in treating the disease in individuals with compromised immune systems (e.g., those with HIV/AIDS [4] ) but also due to the emergence of M. tuberculosis strains that are resistant to one or more of front-line anti-TB drugs. [5] In particular, extremely-drug resistant TB (XDR-TB) has been the subject of substantial recent media coverage [6] stemming in part from an incident [6c] in which an individual, who was thought to be infected with an extreme drug-resistant strain travelled between Europe and North America, potentially infecting large numbers of people.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Substrate Specificity of a Mycobacterial Polyprenol Monophosphomannose‐Dependent α‐(1→6)‐Mannosyltransferase

Tam¹,

Besra²,

Lowary³

2008

ChemBioChem

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A series of synthetic alpha-(1-->6)-linked octyl mannopyranoside oligomers was evaluated as potential acceptors of a polyprenol monophosphomannose-dependent alpha-(1-->6)-mannosyltransferase that is involved in the biosynthesis of the mannan core of mycobacterial lipoarabinomannan. Initial evaluation demonstrated that the enzyme recognizes di-, tri- and tetramannosides (5, 6 and 7) as substrates with different activities. While the highest mannosyltransferase activities were observed when the di- and trisaccharide were used as substrates, diminished enzymatic activity was seen with the tetramannoside. As octyl alpha-D-mannopyranosyl-(1-->6)-alpha-D-mannopyranoside (5) appears to be the minimum structural element required for mannosyltransferase catalysis, a panel of methoxy and deoxy disaccharide analogues (8-21) were used to probe the substrate specificity of the enzyme further. In terms of the steric requirements at the active site, the enzyme does not recognize either C2'- and C2-methoxy analogues as substrates, a result that suggests that the alpha-(1-->2)-mannopyranosyl branches, which are present in the mannan core of LAM must be added on a larger alpha-(1-->6)-oligomannan intermediate. In contrast, the presence of a methoxy functionality at the C3', C3, C4' and C4 positions are somewhat tolerated by the enzyme, although diminished enzyme activities were observed with the C4'- and C4-methoxy analogues. Moreover, the 2'- and 4-hydroxyl groups appear not to be critical for substrate binding at the active site, as both 2'- and 4-deoxy analogues are substrates for the enzyme. In contrast, replacement of the hydroxyl groups at other positions essentially abolished enzymatic activity. Further kinetic characterization of the enzyme by using the effective acceptor substrates gave apparent K(M) values ranging from 111 to 437 microM, which are within two-fold higher or lower than that for the parent dimannoside (5). Although the K(M) values indicate that the enzyme binds those acceptors with comparable affinities, the C4'-methoxy analogue (12) turns over more slowly than the others, as indicated by the apparent V(max) values.

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Section: Optimal Length Of Oligomannopyranosides For Mant a C H T U Nmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the Substrate Specificity of a Mycobacterial Polyprenol Monophosphomannose‐Dependent α‐(1→6)‐Mannosyltransferase

Tam¹,

Besra²,

Lowary³

2008

ChemBioChem

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“…M ycobacterium tuberculosis (Mtb), the leading cause of death from a single bacterial species, severely impacts global health and threatens further havoc with the spread of drug resistance (1). Chemotherapy directed against new classes of targets is an urgent need (2).…”

mentioning

confidence: 99%

Variant tricarboxylic acid cycle in Mycobacterium tuberculosis : Identification of α-ketoglutarate decarboxylase

Tian

Bryk

Itoh

et al. 2005

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

179

171

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Mycobacterium tuberculosis (Mtb) has adapted its metabolism for persistence in the human macrophage. The adaptations are likely to involve Mtb's core intermediary metabolism, whose enzymes have been little studied. The tricarboxylic acid cycle is expected to yield precursors for energy, lipids, amino acids, and heme. The genome sequence of Mtb H37Rv predicts the presence of a complete tricarboxylic acid cycle, but we recently found that ␣-ketoglutarate dehydrogenase (KDH) activity is lacking in Mtb lysates. Here we showed that citrate synthase, aconitase, isocitrate dehydrogenase, fumarase, malate dehydrogenase, and succinate dehydrogenase, but not KDH, are present, raising the possibility of separate oxidative and reductive half-cycles. As a potential link between the half-cycles, we found that Rv1248c, annotated as encoding SucA, the putative E1 component of KDH, instead encodes ␣-ketoglutarate decarboxylase (Kgd) and produces succinic semialdehyde. Succinic semialdehyde dehydrogenase activity was detected in Mtb lysates and recapitulated with recombinant

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“…Hence, the annual incident may increase even with intensive efforts to control the disease (28). Also rate of XDR-TB will increase as a result of synergistic interaction of acquired resistance due to MDR-TB treatment and transmitted resistance (23,29).…”

Section: Discussionmentioning

confidence: 99%

Extensively Drug-Resistant Tuberculosis: A Review Article

Tabarsi

Mardani

2012

Arch Clin Infect Dis

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Extensively Drug-Resistant Tuberculosis (XDR-TB) is a new challenge for Tuberculosis control programs. Lack of effective drugs and high rate of failure in treatment and mortality is a major threat for public health. Treatment of this serious infection needs well-designed individualized dosage regimen and powerful national TB program. In this review we will describe the XDR-TB definition and its epidemiology and will discuss about the treatment options and future opportunities.

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Review: Multidrug‐resistant tuberculosis: public health challenges

Cited by 122 publications

References 55 publications

Exploring the Substrate Specificity of a Mycobacterial Polyprenol Monophosphomannose‐Dependent α‐(1→6)‐Mannosyltransferase

Exploring the Substrate Specificity of a Mycobacterial Polyprenol Monophosphomannose‐Dependent α‐(1→6)‐Mannosyltransferase

Variant tricarboxylic acid cycle in Mycobacterium tuberculosis : Identification of α-ketoglutarate decarboxylase

Extensively Drug-Resistant Tuberculosis: A Review Article

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