XDR Tuberculosis — Implications for Global Public Health

Raviglione, Mario; Smith, Ian M.

doi:10.1056/nejmp068273

Cited by 347 publications

(237 citation statements)

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“…Steady state kinetics of rHg 6 BHSD. A plot of initial velocity against NAD + at fixed DHEA was fitted to equation (5). Conditions: 120 μM DHEA, 100 mM TAPS hydrochloride buffer, 150 mM NaCl, 30 mM MgCl 2 , pH 8.5, 30 °C.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Rv1106c from Mycobacterium tuberculosis Is a 3β-Hydroxysteroid Dehydrogenase

et al. 2007

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New approaches are required to combat M. tuberculosis (Mtb), especially the multi and extremely drug resistant and organisms (MDR-TB and XDR-TB). There are many reports that mycobacteria oxidize 3β-hydroxysterols to 3-ketosteroids, but the enzyme(s) responsible for this activity have not been identified in mycobacterial species. In this work, the Rv1106c gene that is annotated as a 3β-hydroxysteroid dehydrogenase in Mtb has been cloned and heterologously expressed. The purified enzyme was kinetically characterized and found to have a pH optimum between 8.5 and 9.5. The enzyme, which is a member of the short chain dehydrogenase superfamily, uses NAD + as a cofactor and oxidizes cholesterol, pregnenolone and dehydroepiandrosterone to their respective 3-keto-4-ene products. The enzyme forms a ternary complex with NAD + binding before the sterol. The enzyme shows no substrate preference for dehydroepiandrosterone versus pregnenolone with second-order rate constants (k cat /K m ) of 3.2 ± 0.4 μM −1 min −1 and 3.9 ± 0.9 μM −1 min −1 , respectively at pH 8.5, 150 mM NaCl, 30 mM MgCl 2 , and saturating NAD + . Trilostane is a competitive inhibitor of dehydroepiandrosterone with a K i of 197 ± 8 |μM. The expression of the 3β-hydroxysteroid dehydrogenase in Mtb is intracellular. Disruption of the 3β-hydroxysteroid dehydrogenase gene in Mtb abrogates mycobacterial cholesterol oxidation activity. These data are consistent with Rv1106c being the gene responsible for 3β-hydroxysterol oxidation in Mtb.Tuberculosis is an opportunistic infection caused by Mycobacterium tuberculosis (Mtb 1 ) in individuals with HIV-AIDS that is estimated to infect 30% of the world's population (1,2). The World Health Organization estimates that 2 million people die every year from tuberculosis. Drug resistance to front-line Mtb drugs rifampicin and isoniazid has emerged (3,4) and additional resistance to second line drugs is emerging (5,6). It is clear that new approaches are required to combat these multi drug-resistant and extreme (or extensively) drugresistant organisms (7-9).The complete genome sequences of microorganisms are a rich source for mining new drug targets. However, oftentimes, biochemical functions have been assigned to genes purely on the basis of their sequence homology to gene products which are themselves poorly † Financial support from the National Institutes of Health (AI065251 (N.S.S.), AI065997 (I.S.), RR021008, (N.S.S.) and NIAID Contract# HHSN266200400091C, (Colorado State University) and the National Science Foundation (CHE0131146 for NMR spectrometers) is gratefully acknowledged. *corresponding author: Address: Stony Brook University, Stony Brook, New York 11794-3400, Phone: (631) Fax: (631) 632-5731 Nicole.Sampson@StonyBrook.edu. 1 Mtb: Mycobacterium tuberculosis; MDR-TB: multi-drug resistant Mycobacterium tuberculosis; XDR-TB: extremely-drug resistant Mycobacterium tuberculosis; DHEA: dehydroepiandrosterone; rH 6 3BHSD: recombinant 3β-hydroxysteroid dehydrogenase with an Nterminal six histidine tag; rSBHSD...

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Section: Supplementary Materialsmentioning

confidence: 99%

Rv1106c from Mycobacterium tuberculosis Is a 3β-Hydroxysteroid Dehydrogenase

et al. 2007

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“…These drug resistant tuberculosis (DRTB) strains have become a great threat for [2][3] controlling TB from this world.…”

Section: Methodsmentioning

confidence: 99%

Treatment Outcome of Drug Resistance Tuberculosis From a Centre of Eastern Region, Nepal

Ghimire

Rimal

Parajuli

2017

Birat J. Health Sci.

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Introduction Drug resistance tuberculosis (DRTB) has become major problem worldwide with difficulty in treatment. Objective The study is conducted to find the incidence and outcomes of DRTB in one of the eastern tuberculosis treatment centre of Nepal.Methodology We collected all the cases of DRTB being treated from national anti-tuberculosis association of Biratnagar, Nepal. There were altogether 154 patients, who had sputum culture with resistance of at least one anti tubercular drug (ATD), included in this study.Results Of 154 total patients, 36 patients were resistant to rifampicin only, 84 patients were resistant to isoniazid and rifampicin, 18 patients were resistant to isoniazid, rifampicin and ethambutol and 16 patients were resistant to isoniazid, rifampicin and either streptomycin or fluoroquinolone. There was overall 71% cure rate in case of drug resistance tuberculosis. There was only statistical difference between cured and died patients in case of sputum conversion time with earlier sputum conversion in cured patients. Similarly, patients who were previously treated with category 2 ATD had only resistance to ethambutol or streptomycin or fluoroquinolone besides resistance to isoniazid and rifampicin compared to new patients and patients treated with category 1 regimen; as these groups were not found to be resistant to first three drugs.Conclusion There was overall 71% cure rate in case of drug resistance tuberculosis. Earlier sputum conversion was seen in cured patients compared to those who died during the treatment. Multiple drugs were resistant in patients previously treated with category 2 Anti-tubercular drugs.Birat Journal of Health Sciences 2016 1(1): 20-26

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“…1 A majority of individuals in endemic areas are infected with the pathogen Mycobacterium tuberculosis when they reach adulthood. In 2005, around 5 million individuals were diagnosed as having tuberculosis according to a WHO surveillance report.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

et al. 2008

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Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics ¼ 3.01, logarithm of odds (LOD) score ¼ 2.29, empirical P-value ¼ 0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score ¼ 2.57 and 3.33, permutation P-value ¼ 0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.

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XDR Tuberculosis — Implications for Global Public Health

Cited by 347 publications

References 3 publications

Rv1106c from Mycobacterium tuberculosis Is a 3β-Hydroxysteroid Dehydrogenase

Rv1106c from Mycobacterium tuberculosis Is a 3β-Hydroxysteroid Dehydrogenase

Treatment Outcome of Drug Resistance Tuberculosis From a Centre of Eastern Region, Nepal

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

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