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  1. Article: A medicinal chemists’ guide to the unique difficulties of lead optimization for tuberculosis

    Dartois, Véronique / Barry, Clifton E., 3rd

    Bioorganic & medicinal chemistry letters. 2013 Sept. 1, v. 23, no. 17

    2013  

    Abstract: Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium ... ...

    Abstract Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates.
    Keywords bacteria ; chemistry ; chemists ; drugs ; lungs ; tuberculosis
    Language English
    Dates of publication 2013-0901
    Size p. 4741-4750.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2013.07.006
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  2. Article: Tuberculosis: What We Don't Know Can, and Does, Hurt Us

    Russell, David G / Barry, Clifton E. 3rd / Flynn, JoAnne L

    Science. 2010 May 14, v. 328, no. 5980

    2010  

    Abstract: Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. ... ...

    Abstract Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 "high-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention.
    Keywords bacteria ; drug resistance ; host-pathogen relationships ; human population ; humans ; Mycobacterium tuberculosis ; pathogens ; penetrance ; tuberculosis ; vaccines
    Language English
    Dates of publication 2010-0514
    Size p. 852-856.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1184784
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  3. Article: Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein

    Burns, Kristin E / Liu, Wei-Ting / Boshoff, Helena I.M / Dorrestein, Pieter C / Barry, Clifton E. 3rd

    Journal of biological chemistry. 2009 Jan. 30, v. 284, no. 5

    2009  

    Abstract: The striking identification of an apparent proteasome core in Mycobacteria and allied actinomycetes suggested that additional elements of this otherwise strictly eukaryotic system for regulated protein degradation might be conserved. The genes encoding ... ...

    Abstract The striking identification of an apparent proteasome core in Mycobacteria and allied actinomycetes suggested that additional elements of this otherwise strictly eukaryotic system for regulated protein degradation might be conserved. The genes encoding this prokaryotic proteasome are clustered in an operon with a short open reading frame that encodes a small protein of 64 amino acids resembling ubiquitin with a carboxyl-terminal di-glycine-glutamine motif (herein called Pup for prokaryotic ubiquitin-like protein). Expression of a polyhistidine-tagged Pup followed by pulldown revealed that a broad spectrum of proteins were post-translationally modified by Pup. Two-dimensional gel electrophoresis allowed us to conclusively identify two targets of this modification as myoinositol-1-phosphate synthase and superoxide dismutase. Deletion of the penultimate di-glycine motif or the terminal glutamine completely abrogated modification of cellular proteins with Pup. Further mass spectral analysis demonstrated that Pup was attached to a lysine residue on its target protein via the carboxyl-terminal glutamine with deamidation of this residue. Finally, we showed that cell lysates of wild type (but not a proteasome mutant) efficiently degraded Pup-modified proteins. These data therefore establish that, despite differences in both sequence and target linkage, Pup plays an analogous role to ubiquitin in targeting proteins to the proteasome for degradation.
    Language English
    Dates of publication 2009-0130
    Size p. 3069-3075.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
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  4. Article: Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis

    Hugonnet, Jean-Emmanuel / Barry, Clifton E. 3rd / Blanchard, John S / Boshoff, Helena I / Tremblay, Lee W

    Science. 2009 Feb. 27, v. 323, no. 5918

    2009  

    Abstract: β-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of β-lactams are very poor substrates for BlaC, allowing us to determine the three- ... ...

    Abstract β-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of β-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the β-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MICmeropenem) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could potentially be used to treat patients with currently untreatable disease.
    Keywords beta-lactamase ; drug resistance ; drugs ; genes ; meropenem ; minimum inhibitory concentration ; Mycobacterium tuberculosis ; patients
    Language English
    Dates of publication 2009-0227
    Size p. 1215-1218.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1167498
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  5. Article: Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis

    Shi, Wanliang / Clifton E. Barry 3rd / Haiming Yuan / Honghai Wang / Jong Seok Lee / Wenhong Zhang / Xin Jiang / Xuelian Zhang / Ying Zhang

    Science. 2011 Sept. 16, v. 333, no. 6049

    2011  

    Abstract: Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme ... ...

    Abstract Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme frequently lost in PZA-resistant strains, but the target of POA in Mycobacterium tuberculosis has remained elusive. Here, we identify a previously unknown target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Three PZA-resistant clinical isolates without pncA mutation harbored RpsA mutations. RpsA overexpression conferred increased PZA resistance, and we confirmed that POA bound to RpsA (but not a clinically identified ΔAla mutant) and subsequently inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms, and its inhibition may explain the ability of PZA to eradicate persisting organisms.
    Keywords drug therapy ; drugs ; gene overexpression ; mutants ; mutation ; Mycobacterium tuberculosis ; ribosomal proteins ; ribosomes ; translation (genetics) ; tuberculosis
    Language English
    Dates of publication 2011-0916
    Size p. 1630-1632.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1208813
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  6. Article: PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release

    Singh, Ramandeep / Barry, Clifton E. 3rd / Boshoff, Helena I.M / Dowd, Cynthia S / Ha, Young Hwan / Jiricek, Jan / Kang, Sunhee / Keller, Thomas H / Kim, Pilho / Ledwidge, Richard / Lee, Ill Young / Manjunatha, Ujjini / Niyomrattanakit, Pornwaratt / Zhang, Liang

    Science. 2008 Nov. 28, v. 322, no. 5906

    2008  

    Abstract: Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) ... ...

    Abstract Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) that converts PA-824 into three primary metabolites; the major one is the corresponding des-nitroimidazole (des-nitro). When derivatives of PA-824 were used, the amount of des-nitro metabolite formed was highly correlated with anaerobic killing of Mycobacterium tuberculosis (Mtb). Des-nitro metabolite formation generated reactive nitrogen species, including nitric oxide (NO), which are the major effectors of the anaerobic activity of these compounds. Furthermore, NO scavengers protected the bacilli from the lethal effects of the drug. Thus, these compounds may act as intracellular NO donors and could augment a killing mechanism intrinsic to the innate immune system.
    Keywords drugs ; innate immunity ; metabolites ; Mycobacterium tuberculosis ; nitric oxide ; nitroimidazoles ; reactive nitrogen species ; tuberculosis
    Language English
    Dates of publication 2008-1128
    Size p. 1392-1395.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1164571
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  7. Article: Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis

    Madigan, Cressida A / Cheng, Tan-Yun / Layre, Emilie / Young, David C / McConnell, Matthew J / Debono, C. Anthony / Murry, Jeffrey P / Wei, Jun-Rong / Barry, Clifton E., 3rd / Rodriguez, G. Marcela / Matsunaga, Isamu / Rubin, Eric J / Moody, D. Branch

    Proceedings of the National Academy of Sciences of the United States of America. 2012 Jan. 24, v. 109, no. 4

    2012  

    Abstract: To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is ... ...

    Abstract To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is essential for M. tuberculosis survival, and the organism imports this metal using mycobactin and carboxymycobactin siderophores. Detection of an unexpected siderophore variant and deletions of genes for iron scavenging has led to a revised mycobactin biosynthesis model. An organism-wide search of the M. tuberculosis database for hypothetical compounds predicted by this model led to the discovery of two families of previously unknown lipids, designated monodeoxymycobactins and monodeoxycarboxymycobactins. These molecules suggest a revised biosynthetic model that alters the substrates and order of action of enzymes through the mycobactin biosynthetic pathway. We tested this model genetically by solving M. tuberculosis lipidomes after deletion of the iron-dependent regulator (ideR), mycobactin synthase B (mbtB), or mycobactin synthase G (mbtG). These studies show that deoxymycobactins are actively regulated during iron starvation, and also define essential roles of MbtG in converting deoxymycobactins to mycobactin and in promoting M. tuberculosis growth. Thus, lipidomics is an efficient discovery tool that informs genetic relationships, leading to a revised general model for the biosynthesis of these virulence-conferring siderophores.
    Keywords Mycobacterium tuberculosis ; biosynthesis ; data collection ; databases ; enzymes ; genes ; genetic relationships ; lipids ; mass spectrometry ; models ; pathogens ; siderophores ; starvation
    Language English
    Dates of publication 2012-0124
    Size p. 1257-1262.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
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  8. Article: medicinal chemists’ guide to the unique difficulties of lead optimization for tuberculosis

    Dartois, Véronique / Barry, Clifton E., 3rd

    Bioorganic & medicinal chemistry letters

    Volume v. 23,, Issue no. 1

    Abstract: Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium ... ...

    Abstract Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates.
    Keywords tuberculosis ; drugs ; chemistry ; bacteria ; lungs ; chemists
    Language English
    Document type Article
    ISSN 0960-894X
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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