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https://www.readbyqxmd.com/read/29108416/chlorflavonin-targets-acetohydroxyacid-synthase-catalytic-subunit-ilvb1-for-synergistic-killing-of-mycobacterium-tuberculosis
#1
Nidja Rehberg, Herve Sergi Akone, Thomas R Ioerger, German Erlenkamp, Georgios Daletos, Holger Gohlke, Peter Proksch, Rainer Kalscheuer
The flavonoid natural compound chlorflavonin was isolated from the endophytic fungus Mucor irregularis, which was obtained from the Cameroonian medicinal plant Moringa stenopetala. Chlorflavonin exhibited strong growth inhibitory activity in vitro against Mycobacterium tuberculosis (MIC90 1.56 μM) while exhibiting no cytotoxicity towards the human cell lines MRC-5 and THP-1 up to concentrations of 100 µM. Mapping of resistance-mediating mutations employing whole-genome sequencing, chemical supplementation assays, molecular docking studies as well as enzymatic characterization revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase catalytic subunit IlvB1, causing combined auxotrophies to branched chain amino acids and to pantothenic acid...
November 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29069496/interim-outcomes-of-delamanid-for-the-treatment-of-mdr-and-xdr-tb-in-south-korea
#2
Jeongha Mok, Hyungseok Kang, Soo Hee Hwang, Jin Su Park, Bohyoung Kang, Taehoon Lee, Won-Jung Koh, Jae-Joon Yim, Doosoo Jeon
Objectives: Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB. Methods: We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea. Results: A total of 32 patients with MDR-TB, of which 6 (18...
October 23, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29037291/the-devil-we-know-is-the-use-of-injectable-agents-for-the-treatment-of-mdr-tb-justified
#3
A Reuter, P Tisile, D von Delft, H Cox, V Cox, L Ditiu, A Garcia-Prats, S Koenig, E Lessem, R Nathavitharana, J A Seddon, J Stillo, A von Delft, J Furin
For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care...
November 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29025487/incorporating-social-justice-and-stigma-in-cost-effectiveness-analysis-drug-resistant-tuberculosis-treatment
#4
A Zwerling, D Dowdy, A von Delft, H Taylor, M W Merritt
Novel therapies for multidrug-resistant tuberculosis (MDR-TB) are likely to be expensive. The cost of novel drugs (e.g., bedaquiline, delamanid) may be so prohibitively high that a traditional cost-effectiveness analysis (CEA) would rate regimens containing these drugs as not cost-effective. Traditional CEA may not appropriately account for considerations of social justice, and may put the most disadvantaged populations at greater risk. Using the example of novel drug regimens for MDR-TB, we propose a novel methodology, 'justice-enhanced CEA', and demonstrate how such an approach can simultaneously assess social justice impacts alongside traditional cost-effectiveness ratios...
November 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28941848/drug-development-against-tuberculosis-past-present-and-future
#5
REVIEW
Mahesh S Vasava, Manoj N Bhoi, Sanjay K Rathwa, Mayuri A Borad, Sneha G Nair, Hitesh D Patel
Infection of Mycobacterium tuberculosis (MTB) was observed as early as 5000 years ago with evidence, which is a primeval enemy of the humanoid race. MTB is the pathogen which is responsible for causing the infectious disease tuberculosis; it remains a major cause of morbidity and mortality in poor low-income countries as well as in developing countries because of non-availability of reliable laboratory facilities. The current treatment for drug-resistant tuberculosis (TB) is lengthy, complex, and connected with severe harmful side effects and poor outcomes...
October 2017: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-from-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistance
#6
REVIEW
Julie Laborde, Céline Deraeve, Vania Bernardes-Génisson
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy. In the case of prodrugs, the resistance phenomenon is often related to a mutation in the gene encoding for the activation enzymes, resulting thus in a default of these enzymes that are no more able to activate prodrugs...
October 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28887015/bedaquiline-or-delamanid-for-rifampin-resistant-tuberculosis
#7
Erica Lessem, Vivian Cox, Jennifer Furin
No abstract text is available yet for this article.
October 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28840010/delamanid-and-bedaquiline-to-treat-multidrug-resistant-and-extensively-drug-resistant-tuberculosis-in-children-a-systematic-review
#8
REVIEW
Lia D'Ambrosio, Rosella Centis, Simon Tiberi, Marina Tadolini, Margareth Dalcolmo, Adrian Rendon, Susanna Esposito, Giovanni Battista Migliori
The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB...
July 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28826448/clinical-significance-of-qt-prolonging-drug-use-in-patients-with-mdr-tb-or-ntm-disease
#9
H-Y Yoon, K-W Jo, G B Nam, T S Shim
SETTING: Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. OBJECTIVE: To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. METHODS: We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin)...
September 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28821804/nos2-deficient-mice-with-hypoxic-necrotizing-lung-lesions-predict-outcomes-of-tuberculosis-chemotherapy-in-humans
#10
Martin Gengenbacher, Maria A Duque-Correa, Peggy Kaiser, Stefanie Schuerer, Doris Lazar, Ulrike Zedler, Stephen T Reece, Amit Nayyar, Stewart T Cole, Vadim Makarov, Clifton E Barry Iii, Véronique Dartois, Stefan H E Kaufmann
During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 (-/-) mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 (-/-) mice with TB to monotherapy before or after establishment of human-like pathology...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28767036/six-month-response-to-delamanid-treatment-in-mdr-tb-patients
#11
Cathy Hewison, Gabriella Ferlazzo, Zaza Avaliani, Armen Hayrapetyan, Sylvie Jonckheere, Zarema Khaidarkhanova, Erika Mohr, Animesh Sinha, Alena Skrahina, Debrah Vambe, Irina Vasilyeva, Nathalie Lachenal, Francis Varaine
Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.
October 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/28758888/bedaquiline-and-delamanid-combination-treatment-of-5-patients-with-pulmonary-extensively-drug-resistant-tuberculosis
#12
Andrey Maryandyshev, Emanuele Pontali, Simon Tiberi, Onno Akkerman, Shashank Ganatra, Tsetan Dorji Sadutshang, Jan-Willem Alffenaar, Rohit Amale, Jai Mullerpattan, Sonam Topgyal, Zarir Farokh Udwadia, Rosella Centis, Lia D'Ambrosio, Giovanni Sotgiu, Giovanni Battista Migliori
We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.
October 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/28739779/in-vitro-drug-susceptibility-of-bedaquiline-delamanid-linezolid-clofazimine-moxifloxacin-and-gatifloxacin-against-extensively-drug-resistant-tuberculosis-in-beijing-china
#13
Yu Pang, Zhaojing Zong, Fengmin Huo, Wei Jing, Yifeng Ma, Lingling Dong, Yunxu Li, Liping Zhao, Yuhong Fu, Hairong Huang
Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the in vitro susceptibility to bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MFX), and gatifloxacin (GAT) of 90 XDR-TB strains isolated from patients in China. We also describe the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD, and BDQ was found in 82 (91...
October 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28709481/extensively-drug-resistant-tuberculosis-xdr-tb-a-daunting-challenge-to-the-current-end-tb-strategy-and-policy-recommendations
#14
REVIEW
Md Arifur Rahman, Atanu Sarkar
Extensively Drug-resistant Tuberculosis (XDR-TB) has emerged as one of the most formidable challenges to the End TB Strategy that has targeted a 95% reduction in TB deaths and 90% reduction in cases by 2035. Globally, there were an estimated 55,100 new XDR-TB cases in 2015 in 117 countries. However, only one in 30 XDR-TB cases had been reported so far. Drug susceptibility test (DST) is the mainstay for diagnosing XDR-TB, but the lack of laboratory facilities in the resource-limited endemic countries limit its uses...
July 2017: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/28651480/news-on-therapeutic-management-of-mdr-tuberculosis-a-literature-review
#15
Lucie Barthod, Jean-Guillaume Lopez, Christophe Curti, Charléric Bornet, Manon Roche, Marc Montana, Patrice Vanelle
In 2015, the World Health Organization registered 10.4 million people who developed tuberculosis worldwide and 480,000 new cases of multidrug-resistant tuberculosis were identified. The care of multi and extensively drug-resistant tuberculosis is based on a combination of pyrazinamide and second-line drugs. These regimens are lengthy, partially effective and poorly tolerated. The challenge is to re-evaluate the use of existing molecules and to develop new agents more effective against resistant strains with shorter treatment duration...
June 26, 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/28625141/bedaquiline-a-new-hope-for-shorter-and-better-anti-tuberculosis-regimens
#16
Niccolò Riccardi, Filippo Del Puente, Federica Magnè, Lucia Taramasso, Antonio Di Biagio
Background: In 2014, an estimated 1.8 million people died from Mycobacterium tuberculosis (MTB); moreover, 680,000 people developed multidrug-resistant TB (MDR-TB). Methods: Currently available anti-MDR and XDR regimens are long-lasting and expensive, need high adherence and are undermined by a high frequency of adverse drug events, thus leading to a low success rate; moreover, in the last 50 years only two new molecules, bedaquiline (BDQ) and delamanid, have been approved and released for treatment of MDR-TB...
June 19, 2017: Recent Patents on Anti-infective Drug Discovery
https://www.readbyqxmd.com/read/28584788/clinical-implications-of-new-drugs-and-regimens-for-the-treatment-of-drug-resistant-tuberculosis
#17
REVIEW
Yong-Soo Kwon
The emergence of drug-resistant tuberculosis (TB) is a growing problem worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. Therefore, new TB drugs able to bolster the current TB treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multi-drug-resistant (MDR)-TB...
May 2017: Chonnam Medical Journal
https://www.readbyqxmd.com/read/28462832/6-nitro-2-3-dihydroimidazo-2-1-b-1-3-thiazoles-facile-synthesis-and-comparative-appraisal-against-tuberculosis-and-neglected-tropical-diseases
#18
Andrew M Thompson, Adrian Blaser, Brian D Palmer, Robert F Anderson, Sujata S Shinde, Delphine Launay, Eric Chatelain, Louis Maes, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, William A Denny
As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28459575/7-substituted-2-nitro-5-6-dihydroimidazo-2-1-b-1-3-oxazines-novel-antitubercular-agents-lead-to-a-new-preclinical-candidate-for-visceral-leishmaniasis
#19
Andrew M Thompson, Patrick D O'Connor, Andrew J Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, Christopher B Cooper, William A Denny
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28373190/delamanid-kills-dormant-mycobacteria-in-vitro-and-in-a-guinea-pig-model-of-tuberculosis
#20
Xiuhao Chen, Hiroyuki Hashizume, Tatsuo Tomishige, Izuru Nakamura, Miki Matsuba, Mamoru Fujiwara, Ryuki Kitamoto, Erina Hanaki, Yoshio Ohba, Makoto Matsumoto
Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilli in vitro as well as in vivo Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0...
June 2017: Antimicrobial Agents and Chemotherapy
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