DOCSLIB.ORG

Pathway Is Defined (CPTR) : • Preclinical Studies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pathway Is Defined (CPTR) : • Preclinical Studies Shorter TB regimens What is in de pipeline? Martin Boeree, Associate Professor Radboudumc, Nijmegen, the Netherlands Tuesday, 23 September, 2014 Disclosures • Clinical trials and studies funded by EDCTP, BMG, NWO, NACCAP, KNCV • Advisory board Janssen Cilag • Clinical trial drugs donated by Sanofi Outline • Introduction, why shorter treatment? • Resistance • What is in the pipeline? • Repurposed drugs • New drugs • Combinations, trials and expectations • Conclusion Introduction • Shorter treatment is top priority in research • Increases adherence • Decreases emergence of drug resistance • Decrease costs and logistical challenges • For the first time in 40-45 years new drugs are introduced • A clinical pathway is defined (CPTR) : • Preclinical studies. • Animal models (mainly murine), • Phase I, incl MTD studies • Phase II with early bactericidal activity, and 2-3 months to evaluate bacterial response • Finally phase III Ma et al., Lancet, 2010 • The coming years will bring us many phase II and III trials • In this talk an update until today • Problem is the lack of surrogate markers: • Predictors for outcome • Treatment failure • Relapse • Current phase III trials will bring us more knowledge Who are performing clinical trials in TB? • Largest institution to coordinate: GATB = Global Alliance for TB drug Development • www.tballiance.org Other consortia • PanACEA (Pan African Consortium for the Evaluation of AntiTB Antibiotics) ->Europe/Africa • TBTC (TB Trial Consortium) -> USA • ACTG (AIDS Clinical Trial Group) -> USA • InterTB -> UK • MRC CTU -> UK • IUATLD (the Union) -> Global • NIRT(National Institute for TB research) -> India Dakar, October 2013 African PanACEA Partners: Albert-Schweitzer- Makarere University Hospital Tuberculosis Unit NTLP Medical Research Unit IHRDC Bagamoyo - Ifakara KCMC Health Research and Kibong’oto National Developement Centre Tuberculosis Hospital MMRP Mbeya Medical Research Programme UNZA University of Zambia College of Medicine Medical School Blantyre WITS University of Witwatersrand INS AURUM Instituto National de Aurum Institute for Health Saute Research UCT + Stellenbosch University of Cape Town / Stellenbosch See also: • Working Group on New TB Drugs: www.newtbdrugs.org • Treatment Action Group (TAG) pipeline report www.pipelinereport.org Resistance • Not the focus of this talk • In general: a new regimen with new compounds in the future will be as a short as for drug sensitive TB • However, current treatment is far too long now : at least 8 + 12 months, but in many patients even longer • Therefore: some promising shorter treatment developments Developments in shorter MDR treatment regimen • Bangla Desh regimen • STREAM trial (the Standardised Treatment REgimen of Anti-tuberculosis drugs for patients with MDR-TB) = Bangla Desh with high dose moxifloxacin instead of gatifloxacin • Phase III trials • Bedaquiline (in STREAM two extra arms, 28 and 40 weeks, levo instead of moxi because of QT), • PA 824 (Global Alliance) • Delamanid (Otsuka) • More clinical cohort studies: linezolid, thioridazine, cotrimoxazol, ertapenem, etc. Bangla Desh regimen • First 200 patients published in blue journal 2010 • Update on 515 patients. • Observational, not a RCT • 84.4 % bacteriologically favorable outcome • Risk factors for unfavorable outcome • Quinolone resistance • PZA resistance STREAM • Randomization to control (WHO guidelines) and experimental regimen (=modified Bangla Desh regimen) for 9 months • Extension to 10 or 11 months depending on smear status at 4 and 5 months • XDR and pre-XDR excluded • Primary outcome microbiological status at 27 months • N=400 Treatment shortening in drug sensitive TB Compounds under investigation • Established drugs: H, Rifamycins, Z, E ….. • Repurposed drugs: thioridazine, amoxycilline + clavulanic acid, cotrimoxazole, clofazimine, ertapenem, etc. • Novel compounds • TMC207 (bedaquiline) • OPC-67683 (delamanid) • PA-824 • SQ109 • PNU-100480 (sutezolid) • AZT-5847 • Very large number of combinations to test • Must develop regimens not single drugs Rifamycines • Rifampicin HR1, HR2, HIRIF, RIFATOX • Rifapentine study 29, 29 X, plans for phase III HIGHRIF 1 (HR1) study design HR1 study • One control group with standard 10 mg/kg RIF (N=8) • 4 consecutive arms of each 15 patients: • 20 mg RIF/kg • 25 mg RIF/kg • 30 mg RIF/kg • 35 mg RIF/kg CFU (colony forming units) Time CFU EBA: Rate of fall of logCFU per ml of sputum per day Days CFU Fitted estimates of mean baseline log10(CFU)/ml by treatment 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5 -5.0 log10(cfu)/ml,change fitted frombaseline 0 2 4 6 8 10 12 14 Visit Control (10 mg/kg) 20 mg/kg 25 mg/kg 30 mg/kg 35 mg/kg Fitted estimates of difference from mean baseline log10(CFU)/ml by visit and treatment arm from linear fixed effects model with 95% confidence intervals. CFU EBA 0-14 days PK Conclusions • RIF up to 35 mg/kg is safe and tolerated • There is a suggestion of an increasing EBA, especially for 30 and 35 mg/kg • PK: “superproportional” increase in AUC and Cmax (nonlinear PK) without ceiling HR2 – study design Time to culture conversion on MGIT Kaplan-Meier survival estimates 1.00 0.75 0.50 0.25 0.00 0 14 28 42 56 70 84 98 112 126 140 154 analysis time Number at risk dose = 600 48 47 46 39 28 22 14 8 8 8 8 dose = 900 47 46 41 31 23 19 13 7 7 7 7 dose = 1200 47 46 40 28 18 15 12 6 6 6 6 dose = 600 dose = 900 dose = 1200 Conclusions HR2 • Doses of 900 and 1200 mg of RIF combined with standard TB drugs for 2 months are safe and equally well tolerated as the standard dose RIF. • PK shows again a nonlinear, superproportional increase in AUC and Cmax, though less outspoken as in HR1 • Efficacy: modest non-significant difference Conclusions RIFATOX (InterTB and MSF) • 900 and 1200 mg safe and tolerated in 300 patients PanACEA-MAMS-TB-01 Study arms, duration of treatment 3 months: • Control: HRZE INH, rifampicin standard, pyrazinamide, EMB • Arm 1 (R35): HR35ZE INH, rifampicin 35 mg/kg, pyrazinamide, EMB • Arm 2 (Q): HRZQ INH, rifampicin standard, pyrazinamide, SQ109 300 mg • Arm 3 (R20Q): HR20ZQ INH, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg • Arm 4 (R20M): HR20ZM INH, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin N= 382 Rifapentine, study 29 and 29X • Rifapentine: long half life, low MIC • Murine experiments (Nuermberger et al) predict shortening to 3 months • Study 29 • Phase 2 • N=531 • 2HRZE vs 2 HPZE (5 days a week) • Dorman, JID 2013 TBTC Study 29X Phase IIb Dose exploration ● TBTC S29 amendment = TBTC S29 eXtension Study 29 Study 29X n = 531 n = 320 FPI = July 2011 • Open-label • Double-blind for RPT arms • 5/7 + DOTS • 7/7 + DOTS on week days • Fasting • Fed • Primary endpoint: Efficacy & Safety • Primary endpoint: Safety Study 29X, not published yet • Clear dose related increase of 2 months culture conversion up to 100% in the 20 mg/kg arm • Now phase III with high dose rifapentine is planned (study 31) The quinolones 4 • NIRT (Moxifloxacin or Gatifloxacin) •Non-inferiority study • N= 1,931 •Cost: appr. 70 M$ •Took about 10 years REMox REMox favorable outcome REMox unfavorable outcome Rifaquin N= 827 • standard control regimen 2HRZE/4HR • 2EMRZ/2 months twice a week moxifloxacin 400 mg, rifapentine 900 mg • 2EMRZ/4 months moxifloxacin 400 mg, rifapentine 1200 mg once weekly Conclusion: 4 months inferior, 6 months non-inferior Not published yet Oflotub • N=1836 • 2HRZG/2HRG (G=gatifloxacin) • standard control regimen 2HRZE/4HR • 2 months culture conversion rates no difference • 4 months no non-inferiority demonstrated, large variation by country and HIV status • Not published yet NIRT, Chennai and Madurai, India • Three times a week gatifloxacin or moxifloxacin, N= 416 NIRT • High culture conversion rates at the end of treatment in all arms • Gati 95% • Moxi 98% • Control 97% • High proportion of culture conversion at two months • Gati 83% • Moxi 88% • Control 78% • High relapse rates until 24 months post treatment • Gati 16 % • Moxi 10% • Control 6 % • Trial was prematurely stopped by DSMB! Conclusions from the four quinolone phase III trials • 4 months is not (yet) acceptable enough though relapse rates are relatively low • Murine models have overpredicted sterile capacity of quinolones • Bacterial load markers, such as time to culture conversion do not adequately predict long term outcome. • We need markers that predict relapse!! Surrogate markers for sterilizing capacity (for relapse), are they there? What else? Old compounds • Pyrazinamide: dose probably too low • Isoniazide: high doses show efficacy in MDRTB • Clofazimine • Thioridazine • Cotrimoxazol, amoxycilline/clavulanic acid, etcetera H37Rv H37Rv Infection Control Plus infection Thioridazine (B) In contrast, less (A) Extensive lung consolidation pneumonia (arrow) (arrows) is visible in is seen in the lung of control animals after Mice treated with 120 days of infection Thioridazine 32 mg/kg by drug-sensitive daily by intragastric cannula. control Strain H37Rv. MDR MDR Infection Control Plus Infection Thioridazine (C) Control mice after 120 In comparison, less lung days of infection consolidation (arrow) is seen with MDR strain in the lung of mice infected by show extensive the MDR-TB strain and pneumonic areas treated daily during two (arrow) months with 70 mg/kg of thioridazine Clofazimine • A riminophenazine derivative, seems to be very bactericidal in mice, used long time for leprosy, side effects skin coloration + gastrointestinal discomfort + QT prolongation • EBA 0-14 (Paris october 2013): none • Was used in the “Bangladesh”
Load more

Recommended publications
  • SQ109 for the Treatment of Tuberculosis Clinical Development Status: Phase 2
    SQ109 for the Treatment of Tuberculosis Clinical Development Status: Phase 2 Since 2000, Sequella has applied its scientific expertise in tuberculosis (TB) research to develop SQ109, a promising drug candidate that was discovered in partnership with the National Institutes of Health in a screen for activity against M. tuberculosis (Mtb). SQ109 was selected as best in class from a 63,000 compound library of diamines and underwent extensive preclinical studies in rats, dogs, keys and mon . It was safe and well-­‐tolerated in three Phase 1 clinical trials, and a Phase 2 clinical trial was completed in late . 2011 TB is a public health crisis and unmet medical need. TB is the cause of the largest number of human deaths attributable to a single etiologic agent, killing nearly 2 million people each year. The poor efficacy of existing TB drugs requires that they be administered in a multidrug regimen for at least six months. This results in poor patient compliance and leads to development of multidrug-­‐ resistant TB (MDR-­‐TB) and extremely drug-­‐resistant TB (XDR-­‐TB). MDR-­‐TB and XDR-­‐TB are even more difficult to treat (5-­‐8 drugs for up to 24 months) and have significantly higher mortality. Decades of misuse of existing antibiotics and poor ance compli have created an epidemic of drug resistance that threatens TB control programs worldwide. New drugs and treatment regimens with activity against drug-­‐susceptible and drug-­‐resistant TB are desperately needed to manage this public health crisis. SQ109 has promising activity against drug-­‐susceptible and drug-­‐resistant Me Me TB.
    [Show full text]
  • Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.27.269936; this version posted August 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450 a,1 b,1 b a b Sergey Bukhdruker , Tatsiana Varaksa , Irina Grabovec , Egor Marin , Polina Shabunya , Maria Kadukovaa,c, Sergei Grudininc, Anton Kavaleuskib, Anastasiia Gusacha , Andrei Gilepb,d,e, Valentin Borshchevskiya,f,g,2, Natallia Strushkevichb,h,2 aResearch Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia. bInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus. c Université Grenoble Alpes, CNRS, Inria, Grenoble INP, LJK, Grenoble, France. dInstitute of Biomedical Chemistry, Moscow, Russia. eMT-Medicals LLC, Moscow, Russia. fInstitute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany. gJuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany. hSkolkovo Institute of Science and Technology, Moscow, Russia. 1these authors contributed equally to this work 2corresponding authors: [email protected]; [email protected] Keywords: cytochrome P450, crystal structure, Mycobacterium tuberculosis, SQ109, CYP124 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.27.269936; this version posted August 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Spreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs.
    [Show full text]
  • Sequella Initiates Phase I Clinical Trial for Sq109
    Sequella, Inc. 9610 Medical Center Drive Rockville, MD 20850 Tele: 301-762-7776 www.sequella.com NEWS RELEASE October 3, 2006 SEQUELLA INITIATES PHASE I CLINICAL TRIAL FOR SQ109 Patient Dosed with Company’s First Clinical Drug Candidate ROCKVILLE, MD – Sequella, Inc., a clinical-stage biopharmaceutical company focused on commercializing improved treatment paradigms for diseases of epidemic potential announced today it has initiated a Phase I clinical trial for SQ109, the Company’s lead drug candidate for the treatment of tuberculosis (TB). With a mechanism of action distinct from other antibiotics used in TB therapy (including Isoniazid, Ethambutol and Ethionamide), SQ109 inhibits cell wall synthesis in a select group of microorganisms with excellent in vitro activity against both drug susceptible and drug resistant TB bacteria, including XDR-TB. The first clinical trial dose of SQ109 was administered at the Quintiles Clinical Pharmacology Unit in Lenexa, Kansas. “We believe that SQ109 may establish a new therapeutic standard-of-care for patients with TB,” said Dr. Carol A. Nacy, CEO of Sequella. “Based on preclinical data, SQ109 has the potential to improve outcome and shorten the current treatment regimen when combined with several first- line TB drugs. SQ109 – with more accurate diagnosis provided by Sequella TB Patch – may represent an important step forward in quickly detecting active TB, more effectively treating infected patients, and ultimately reducing the spread of disease.” This Phase 1 dose-escalation study is enrolling 46 healthy normal volunteers. The patients will be divided into five ascending dose groups of eight, plus an additional group of six in an effect of food group, to evaluate the safety and pharmacokinetics of SQ109.
    [Show full text]
  • Mycobacterium Tuberculosis Drug Resistance
    Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model Aleidy Silvaa,1, Bai-Yu Leeb,1, Daniel L. Clemensb,1, Theodore Keec, Xianting Dingd, Chih-Ming Hoa,c,2, and Marcus A. Horwitzb,2 aDepartment of Mechanical and Aerospace Engineering, University of California, Los Angeles, CA 90095; bDivision of Infectious Diseases, Department of Medicine, University of California, Los Angeles, CA 90095; cDepartment of Bioengineering, University of California, Los Angeles, CA 90095; and dMed-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China Edited by Barry R. Bloom, Harvard School of Public Health, Boston, MA, and approved February 23, 2016 (received for review January 22, 2016) Tuberculosis (TB) remains a major global public health problem, and potential drug combinations. The first effective TB drug, strep- improved treatments are needed to shorten duration of therapy, tomycin (STR), was introduced in 1944, but used as monotherapy, decrease disease burden, improve compliance, and combat emer- resistance to it developed readily. Combination therapy with gence of drug resistance. Ideally, the most effective regimen would additional drugs, such as isoniazid (INH), para-aminosalicylic be identified by a systematic and comprehensive combinatorial search acid (PAS), and ethambutol (EMB), reduced the problem of of large numbers of TB drugs. However, optimization of regimens drug resistance, but lengthy treatments of 18–24 mo were re- by standard methods is challenging, especially as the number of drugs quired. In the 1970s, the addition of rifampicin (RIF) to the increases, because of the extremely large number of drug–dose com- regimen of STR, INH, and EMB allowed a shortening of binations requiring testing.
    [Show full text]
  • MULTI-TARGET DRUG DISCOVERY AGAINST STAPHYLOCOCCUS AUREUS and TRYPANOSOMA BRUCEI INFECTIONS by YANG WANG DISSERTATION Submitted
    MULTI-TARGET DRUG DISCOVERY AGAINST STAPHYLOCOCCUS AUREUS AND TRYPANOSOMA BRUCEI INFECTIONS BY YANG WANG DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2016 Urbana, Illinois Doctoral Committee: Professor Eric Oldfield, Chair Professor Robert B. Gennis Professor Paul J. Hergenrother Professor Steven C. Zimmerman Abstract The drug resistance has become a big threat to human health, and there is currently a dearth of new antibiotics being introduced. In order to find novel potent antibiotics against Staphylococcus aureus, a series of amidine and bisamidine compounds were synthesized and investigated against Staphylococcus aureus. The most active compounds are potent inhibitors against undecaprenyl diphosphate synthase (UPPS), an essential enzyme involved in cell wall biosynthesis pathway. Besides, they bound to an AT-rich DNA dodecamer (CGCGAATTCGCG)2 and were found to increase the melting transition by up to 24 °C using differential scanning calorimetry (DSC). Good correlations (R2 = 0.89, S. aureus) were found between experimental and predicted cell growth inhibition by using DNA ΔTm and UPPS IC50 experimental results together with one computed descriptor. We also solved the structures of three bisamidines binding to DNA as well as three UPPS structures. Overall, the results are of general interest in the context of the development of resistance-resistant antibiotics that involve multi-targeting. To extend the potential utility of this class of amidine compound, we tested them against Trypanosoma brucei, the causative agent of human African trypanosomiasis. The most active compound was a biphenyldiamidine which had an EC50 of 7.7 nM against bloodstream form parasites.
    [Show full text]
  • Global Tuberculosis Drug Development Pipeline: the Need and the Reality
    Series Tuberculosis 5 Global tuberculosis drug development pipeline: the need and the reality Zhenkun Ma, Christian Lienhardt, Helen McIlleron, Andrew J Nunn, Xiexiu Wang Drugs for tuberculosis are inadequate to address the many inherent and emerging challenges of treatment. In the past Published Online decade, ten compounds have progressed into the clinical development pipeline, including six new compounds May 19, 2010 DOI:10.1016/S0140- specifically developed for tuberculosis. Despite this progress, the global drug pipeline for tuberculosis is still insufficient 6736(10)60359-9 to address the unmet needs of treatment. Additional and sustainable efforts, and funding are needed to further improve This is the fifth in a Series of the pipeline. The key challenges in the development of new treatments are the needs for novel drug combinations, new eight papers about tuberculosis trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and Global Alliance for TB Drug biomarkers for prediction of long-term outcome. Despite substantial progress in efforts to control tuberculosis, the Development, New York, NY, global burden of this disease remains high. To eliminate tuberculosis as a public health concern by 2050, all responsible USA (Z Ma PhD); Stop TB parties need to work together to strengthen the global antituberculosis drug pipeline and support the development of Partnership Secretariat, Stop TB Department, WHO, Geneva, new antituberculosis drug regimens. Switzerland (C Lienhardt PhD); Division of Clinical Introduction this study suggest that the combination of a 2-month Pharmacology, Department of Rifampicin, discovered 40 years ago, represents the last treatment regimen that cures 95% of MDR tuberculosis, Medicine, University of Cape Town, Cape Town, South Africa novel class of antibiotics introduced for the first-line a generalised nucleic acid amplification test, and a joint (H McIlleron PhD); Medical treatment of tuberculosis.
    [Show full text]
  • Public Health Reviews
    Public Health Reviews Treatment of tuberculosis: present status and future prospects Philip Onyebujoh,1 Alimuddin Zumla,2 Isabella Ribeiro,1 Roxana Rustomjee,3 Peter Mwaba,4 Melba Gomes,1 & John M. Grange 2 Abstract Over recent years, tuberculosis (TB) and disease caused by human immunodeficiency virus (HIV) have merged in a synergistic pandemic. The number of new cases of TB is stabilizing and declining, except in countries with a high prevalence of HIV infection. In these countries, where HIV is driving an increase in the TB burden, the capacity of the current tools and strategies to reduce the burden has been exceeded. This paper summarizes the current status of TB management and describes recent thinking and strategy adjustments required for the control of TB in settings of high HIV prevalence. We review the information on anti-TB drugs that is available in the public domain and highlight the need for continued and concerted efforts (including financial, human and infrastructural investments) for the development of new strategies and anti-TB agents. Keywords Tuberculosis, Multidrug-resistant/drug therapy; Antitubercular agents/administration and dosage/adverse effects; Directly observed therapy; Drug therapy/trends; Drug combinations; Quinolones; Quinoline; Nitroimidazoles; Quinolizines; HIV infections/drug therapy; Evaluation studies (source: MeSH, NLM). Mots clés Tuberculose résistante à la polychimiothérapie /chimiothérapie; Antituberculeux/administration et posologie/effets indésirables; Thérapie sous observation directe; Chimiothérapie/orientations;
    [Show full text]
  • Tuberculosis Drug Information Guide, 2Nd Edition
    Tuberculosis Drug Information Guide 2ND EDITION Edmund G. Brown Jr, Governor STATE OF CALIFORNIA Diana S. Dooley, Secretary CALIFORNIA HEALTH & HUMAN SERVICES AGENCY Ron Chapman, MD, MPH, Director DEPARTMENT OF PUBLIC HEALTH Tuberculosis Drug Information Guide 2ND EDITION Edmund G. Brown Jr, Governor STATE OF CALIFORNIA Diana S. Dooley, Secretary CALIFORNIA HEALTH & HUMAN SERVICES AGENCY Ron Chapman, MD, MPH, Director DEPARTMENT OF PUBLIC HEALTH DrugInfo_2ndEd_v9.indd 3 12/5/12 3:55 PM Tuberculosis Drug Information Guide, 2nd edition was created through a collaboration of the Curry International Tuberculosis Center (CITC) and the State of California Department of Public Health, Tuberculosis Control Branch (CDPH). CITC is a project of the University of California, San Francisco, funded by the Centers for Disease Control and Prevention (CDC). The development of this Guide was funded through CDC Cooperative Agreement U52 CCU 900454. Permission is granted for nonprofit educational use and library duplication and distribution. Suggested citation: Curry International Tuberculosis Center and California Department of Public Health, 2012: Tuberculosis Drug Information Guide, 2nd edition. This publication is available on the CITC website: http://www.currytbcenter.ucsf.edu/ tbdruginfo/ Design: Edi Berton Design DrugInfo_2ndEd_v9.indd 4 12/5/12 3:55 PM Contributors Acknowledgments Ann M. Loeffler, MD John S. Bradley, MD Pediatric Infectious Diseases Attending and Director of Pediatric Rady Children’s Hospital San Diego, San Diego, California Hospitalists at Randall Children’s Hospital at Legacy Emanuel, Daniel Deck, Pharm.D. Portland, Oregon Department of Pharmaceutical Services, Pediatric Tuberculosis Consultant, San Francisco General Hospital, California Curry International Tuberculosis Center, San Francisco, California David Forinash, RPh Randall Children’s Hospital at Legacy Emanuel, Portland, Oregon Charles A.
    [Show full text]
  • Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450
    International Journal of Molecular Sciences Article Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450 1,2,3, , 4, 4 1 Sergey Bukhdruker y z , Tatsiana Varaksa y , Irina Grabovec , Egor Marin , Polina Shabunya 4, Maria Kadukova 1,5 , Sergei Grudinin 5, Anton Kavaleuski 4, Anastasiia Gusach 1,§, Andrei Gilep 4,6,7, Valentin Borshchevskiy 1,2,3,* and Natallia Strushkevich 4,8,* 1 Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia; [email protected] (S.B.); [email protected] (E.M.); [email protected] (M.K.); [email protected] (A.G.) 2 Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, 52428 Jülich, Germany 3 JuStruct: Jülich Center for Structural Biology, Research Center Jülich, 52428 Jülich, Germany 4 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus; [email protected] (T.V.); [email protected] (I.G.); [email protected] (P.S.); [email protected] (A.K.); [email protected] (A.G.) 5 Grenoble Alpes University, CNRS, Inria, Grenoble INP, LJK, 38000 Grenoble, France; [email protected] 6 Department of Proteomic Research and Mass Spectrometry, Institute of Biomedical Chemistry, 119435 Moscow, Russia 7 R&D Department, MT-Medicals LLC, 121205 Moscow, Russia 8 Center for Computational and Data-Intensive Science and Engineering (CDISE), Skolkovo Institute of Science and Technology, 121205 Moscow, Russia * Correspondence: [email protected] (V.B.); [email protected] (N.S.); Tel.: +7-964-632-8650 (V.B.); +7-985-699-1410 (N.S.) These authors contributed equally to this work.
    [Show full text]
  • Tuberculosis: the Drug Development Pipeline at a Glance Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain Baulard, Benoit Déprez, Nicolas Willand
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archive Ouverte en Sciences de l'Information et de la Communication Tuberculosis: The drug development pipeline at a glance Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain Baulard, Benoit Déprez, Nicolas Willand To cite this version: Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain Baulard, Benoit Déprez, et al.. Tuberculosis: The drug development pipeline at a glance. European Journal of Medicinal Chemistry, Elsevier, 2012, 51, pp.1-16. 10.1016/j.ejmech.2012.02.033. hal-02309791 HAL Id: hal-02309791 https://hal.archives-ouvertes.fr/hal-02309791 Submitted on 9 Oct 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Tuberculosis: The drug development pipeline at a glance Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain Baulard, Benoit Déprez, Nicolas Willand To cite this version: Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain Baulard, Benoit Déprez, et al.. Tuberculosis: The drug development pipeline at a glance. European Journal of Medicinal Chemistry, 2012, 51, pp.1- 16. 10.1016/j.ejmech.2012.02.033. hal-02309791 HAL Id: hal-02309791 https://hal.archives-ouvertes.fr/hal-02309791 Submitted on 9 Oct 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not.
    [Show full text]
  • Mechanisms of Drug Resistance in Mycobacterium Tuberculosis: Update 2015
    INT J TUBERC LUNG DIS 19(11):1276–1289 STATE OF THE ART Q 2015 The Union http://dx.doi.org/10.5588/ijtld.15.0389 Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015 Y. Zhang,* W-W. Yew† *Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; †Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong SAR, China SUMMARY Drug-resistant tuberculosis (DR-TB), including multi- resistance. However, further research is needed to and extensively drug-resistant TB, is posing a significant address the significance of newly discovered gene challenge to effective treatment and TB control world- mutations in causing drug resistance. Improved knowl- wide. New progress has been made in our understanding edge of drug resistance mechanisms will help understand of the mechanisms of resistance to anti-tuberculosis the mechanisms of action of the drugs, devise better drugs. This review provides an update on the major molecular diagnostic tests for more effective DR-TB advances in drug resistance mechanisms since the management (and for personalised treatment), and previous publication in 2009, as well as added informa- facilitate the development of new drugs to improve the tion on mechanisms of resistance to new drugs and treatment of this disease. repurposed agents. The recent application of whole KEY WORDS: antibiotics; drug resistance; mechanisms; genome sequencing technologies has provided new molecular diagnostics; new drugs insight into the mechanisms and complexity of drug The use of multiple-drug therapy, although defi- drug-resistant TB (DR-TB) epidemic thus remains nitely beneficial, is not an absolute guarantee an alarming problem, and is further aggravated by against the emergence of drug-resistant in- human immunodeficiency virus (HIV) coinfection.3 fections.
    [Show full text]
  • Dissertation Mycobacterial Arabinan Biosynthesis
    DISSERTATION MYCOBACTERIAL ARABINAN BIOSYNTHESIS: CHARACTERIZATION OF AftB AND AftC ARABINOSYLTRANSFERASE ACTIVITY USING SYNTHETIC SUBSTRATES Submitted by Shiva kumar Angala Department of Microbiology, Immunology and Pathology In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Fall 2011 Doctoral Committee: Advisor: Delphi Chatterjee Co-Advisor: Dean C. Crick Herbert P. Schweizer Norman P. Curthoys ABSTRACT MYCOBACTERIAL ARABINAN BIOSYNTHESIS: CHARACTERIZATION OF AftB AND AftC ARABINOSYLTRANSFERASE ACTIVITY USING SYNTHETIC SUBSTRATES Tuberculosis (TB) is a chronic infectious disease caused by M. tuberculosis (Mtb). Treatment of TB is prolonged, and multidrug resistant (MDR-TB) and extensively drug resistant TB (XDR-TB) cases are ever increasing. Efforts to discover and develop new drugs have increased in recent years so improvement of the existing therapies is urgently needed. The cell wall of Mtb with its unique physiological properties has historically been an important and valid drug target. Mycobacterial arabinosyltransferases are membrane bound glycosyltransferases involved in the biosynthesis of the arabinan portion of two major polysaccharides, arabinogalactan (AG) and lipoarabinomannan (LAM), associated with the cell wall. In this work, M. smegmatis was used as a model organism to study arabinosyltransferases and the biosynthesis of cell wall arabinofuran— the main constituent of AG and LAM. This dissertation addresses the development of a cell free arabinosyltransferase assay for AftB and AftC glycosyltransferases. Since it was not possible to express AftB transmembrane protein, we probed AftB transferase activity from the crude membranes using a synthetic arabinose disaccharide acceptor. In this study, a robust cell free ii radioactive arabinosyltransferase assay was developed using a linkage specific synthetic disaccharide acceptor.
    [Show full text]