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Journal ArticleDOI

A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.

TL;DR: A diarylquinoline, R207910, is identified that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
Abstract: The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 μg/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
Citations
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Journal ArticleDOI
TL;DR: Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease Key Laboratory Features of N TM Health Careand Hygiene-associated Disease Prevention Prophylaxis and Treatment of NTM Disease Introduction Methods.
Abstract: Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease Key Laboratory Features of NTM Health Careand Hygiene-associated Disease Prevention Prophylaxis and Treatment of NTM Disease Introduction Methods Taxonomy Epidemiology Pathogenesis Host Defense and Immune Defects Pulmonary Disease Body Morphotype Tumor Necrosis Factor Inhibition Laboratory Procedures Collection, Digestion, Decontamination, and Staining of Specimens Respiratory Specimens Body Fluids, Abscesses, and Tissues Blood Specimen Processing Smear Microscopy Culture Techniques Incubation of NTM Cultures NTM Identification Antimicrobial Susceptibility Testing for NTM Molecular Typing Methods of NTM Clinical Presentations and Diagnostic Criteria Pulmonary Disease Cystic Fibrosis Hypersensitivity-like Disease Transplant Recipients Disseminated Disease Lymphatic Disease Skin, Soft Tissue, and Bone Disease

4,969 citations


Cites background from "A diarylquinoline drug active on th..."

  • ...With the recent unprecedented introduction of several promising agents for the treatment of TB, there is some hope that there will be collateral benefit for the therapy of NTM disease as well (447)....

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Journal ArticleDOI
21 Jul 2011-Nature
TL;DR: A DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes, showing its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
Abstract: The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.

2,246 citations

Journal ArticleDOI
TL;DR: The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
Abstract: The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.

2,228 citations


Cites background from "A diarylquinoline drug active on th..."

  • ...pneumoniae to the atpC subunit of theF 0 F 1 ATPase, a target limited in essentiality to selected pathogens including some streptococci and Mycobacterium tuberculosis...

    [...]

Journal ArticleDOI
TL;DR: Next-generation sequencing technologies are surveyed and it is considered how they can provide a more complete picture of how the genome shapes the organism.

2,177 citations


Cites background from "A diarylquinoline drug active on th..."

  • ...A remarkable study by an international consortium used 454 sequencing of Mycobacterium tuberculosis to identify drug targets of a diarylquinoline drug that potently inhibited both drugsensitive and -resistant strains of the pathogen [ 21 ]....

    [...]

Journal ArticleDOI
TL;DR: A new generation of non-Sanger-based sequencing technologies has delivered on its promise of sequencing DNA at unprecedented speed, thereby enabling impressive scientific achievements and novel biological applications.
Abstract: A new generation of non-Sanger-based sequencing technologies has delivered on its promise of sequencing DNA at unprecedented speed, thereby enabling impressive scientific achievements and novel biological applications. However, before stepping into the limelight, next-generation sequencing had to overcome the inertia of a field that relied on Sanger-sequencing for 30 years.

1,736 citations

References
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Journal ArticleDOI
TL;DR: This work has derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins, leading to marked improvements in alignments and in searches using queries from each of the groups.
Abstract: Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.

6,553 citations

Journal ArticleDOI
TL;DR: The prevention of HIV and TB, the extension of WHO DOTS programs, and a focused effort to control HIV-related TB in areas of high HIV prevalence are matters of great urgency.
Abstract: BACKGROUND: The increasing global burden of tuberculosis (TB) is linked to human immunodeficiency virus (HIV) infection. METHODS: We reviewed data from notifications of TB cases, cohort treatment outcomes, surveys of Mycobacterium tuberculosis infection, and HIV prevalence in patients with TB and other subgroups. Information was collated from published literature and databases held by the World Health Organization (WHO), the Joint United Nations Programme on HIV/Acquired Immunodeficiency Syndrome (UNAIDS), the US Census Bureau, and the US Centers for Disease Control and Prevention. RESULTS: There were an estimated 8.3 million (5th-95th centiles, 7.3-9.2 million) new TB cases in 2000 (137/100,000 population; range, 121/100,000-151/100,000). Tuberculosis incidence rates were highest in the WHO African Region (290/100,000 per year; range, 265/100,000-331/100,000), as was the annual rate of increase in the number of cases (6%). Nine percent (7%-12%) of all new TB cases in adults (aged 15-49 years) were attributable to HIV infection, but the proportion was much greater in the WHO African Region (31%) and some industrialized countries, notably the United States (26%). There were an estimated 1.8 million (5th-95th centiles, 1.6-2.2 million) deaths from TB, of which 12% (226 000) were attributable to HIV. Tuberculosis was the cause of 11% of all adult AIDS deaths. The prevalence of M tuberculosis-HIV coinfection in adults was 0.36% (11 million people). Coinfection prevalence rates equaled or exceeded 5% in 8 African countries. In South Africa alone there were 2 million coinfected adults. CONCLUSIONS: The HIV pandemic presents a massive challenge to global TB control. The prevention of HIV and TB, the extension of WHO DOTS programs, and a focused effort to control HIV-related TB in areas of high HIV prevalence are matters of great urgency.

2,762 citations

Journal ArticleDOI
TL;DR: A review of studies that measured compliance using EM confirmed that the prescribed number of doses per day is inversely related to compliance.

2,311 citations

Journal ArticleDOI
TL;DR: Investigators need to become better acquainted with statistical techniques for making multiple comparisons and use inappropriate statistical methods to analyze the differences between group means.
Abstract: This article discusses statistical methods for comparing the means of several groups and focuses on examples from 50 Original Articles published in the Journal in 1978 and 1979. Although medical authors often present comparisons of the means of several groups, the most common method of analysis, multiple t-tests, is usually a poor choice. Which method of analysis is appropriate depends on what questions the investigators wish to ask. If the investigators want to identify which of the groups under study are different from the rest, they will need a different method from the one required if they wish simply to decide whether or not the groups share a common mean. More complicated questions about the group means call for more sophisticated techniques. Of the 50 Journal articles examined, 27 (54 per cent) used inappropriate statistical methods to analyze the differences between group means. Investigators need to become better acquainted with statistical techniques for making multiple comparisons betw...

712 citations

Journal ArticleDOI
TL;DR: In this article, the authors discuss statistical methods for comparing the means of several groups and focus on examples from 50 original articles published in the Journal in 1978 and 1979, and conclude that the most common method of analysis, multiple t-tests, is usually a poor choice.
Abstract: This article discusses statistical methods for comparing the means of several groups and focuses on examples from 50 Original Articles published in the Journal in 1978 and 1979. Although medical authors often present comparisons of the means of several groups, the most common method of analysis, multiple t-tests, is usually a poor choice. Which method of analysis is appropriate depends on what questions the investigators wish to ask. If the investigators want to identify which of the groups under study are different from the rest, they will need a different method from the one required if they wish simply to decide whether or not the groups share a common mean. More complicated questions about the group means call for more sophisticated techniques. Of the 50 Journal articles examined, 27 (54 per cent) used inappropriate statistical methods to analyze the differences between group means. Investigators need to become better acquainted with statistical techniques for making multiple comparisons between group means.

539 citations

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