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Jingjing Luo, Xia Yu, Guanglu Jiang, Yuhong Fu, Fengmin Huo, Yifeng Ma, Fen Wang, Yuanyuan Shang, Qian Liang, Yi Xue, Hairong Huang
Due to the natural resistance of non-tuberculous mycobacteria(NTM) to lots of antibiotics,treatment of diseases caused by NTM is often long-termed but less successful.The main goal of this study was to evaluate the in vitro susceptibility to clofazimine of 209 isolates consisting of different NTM species isolated in Beijing,China. Furthermore,47 reference strains were also tested, including 30 rapidly growing mycobacterium (RGM) species and 17 slowly growing mycobacterium(SGM) species.The potential molecular mechanism contributing to clofazimine resistance of NTM was investigated as well...
May 14, 2018: Antimicrobial Agents and Chemotherapy
Robert S Wallis, Caryn E Good, Mary A O'Riordan, Jeffrey L Blumer, Michael R Jacobs, J McLeod Griffiss, Amanda Healan, Robert A Salata
BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture...
2018: PloS One
Ji-A Jeong, Sae Woong Park, Dahae Yoon, Suhkmann Kim, Ho-Young Kang, Jeong-Il Oh
Here we demonstrated that the inhibition of electron flux through the respiratory electron transport chain (ETC) by either disruption of the gene for the major terminal oxidase ( aa3 -cytochrome c oxidase) or treatment with KCN resulted in the induction of ald encoding alanine dehydrogenase in Mycobacterium smegmatis A decrease in functionality of the ETC shifts the redox state of the NADH/NAD+ pool toward a more reduced state, which in turn leads to an increase in cellular levels of alanine by Ald catalyzing the conversion of pyruvate to alanine with the concomitant oxidation of NADH to NAD+ The induction of ald expression under respiration-inhibitory conditions in M...
April 30, 2018: Journal of Bacteriology
Bing Li, Meiping Ye, Qi Guo, Zhemin Zhang, Shiyi Yang, Wei Ma, Fangyou Yu, Haiqing Chu
Chemotherapeutic options are very limited against Mycobacterium abscessus infections. Bedaquiline, a new anti-tuberculosis drug, is effective for the treatment of multidrug-resistant TB. However, little data is available on bedaquiline in treating M. abscessus infections. In this study, we reported the in vitro susceptibility profile of M. abscessus clinical isolates to bedaquiline and investigated the potential molecular mechanisms of decreased susceptibility. A total of 197 M. abscessus clinical isolates were collected from sputum and bronchoalveolar fluid of patients with lung infections...
April 30, 2018: Antimicrobial Agents and Chemotherapy
Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Suzette Oelofse, Phindile Gina, Elize Pietersen, Mohammed Fadul, Rob Warren, Keertan Dheda
No abstract text is available yet for this article.
April 26, 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
M Murali Krishna Kumar, J Risy Namratha, K Purna Nagasree, G P V Sangeeta
Morbidity and mortality due to tuberculosis is rising steadily. Despite having efficient drugs and treatment protocols, microbial drug resistance is often leading to treatment failure. Efforts to bring novel drugs to combat this menace are hampered by several issues including problems in gaining industry support, motivation and ethical issues clinical trials. Bedaquiline and Delaminid are the only novel drugs approved in the last three decades for treating TB. A few more molecules and drug combinations are still in clinical trials...
April 22, 2018: Current Computer-aided Drug Design
A J Garcia-Prats, E M Svensson, E D Weld, H S Schaaf, A C Hesseling
After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
N Bionghi, A Daftary, B Maharaj, Z Msibi, K R Amico, G Friedland, C Orrell, N Padayatchi, M R O'Donnell
BACKGROUND: The introduction of Bedaquiline, the first new antimycobacterial drug in over 40 years, has highlighted the critical importance of medication adherence in drug-resistant tuberculosis (DR-TB) treatment to prevent amplified drug-resistance and derive sustained benefit. Real-time electronic dose monitoring (EDM) accurately measures adherence and allows for titration of adherence support for anti-retroviral therapy (ART). The goal of this study was to evaluate the accuracy and acceptability of a next-generation electronic pillbox (Wisepill RT2000) for Bedaquiline-containing TB regimens...
April 11, 2018: BMC Infectious Diseases
Simon Tiberi, Nelita du Plessis, Gerhard Walzl, Michael J Vjecha, Martin Rao, Francine Ntoumi, Sayoki Mfinanga, Nathan Kapata, Peter Mwaba, Timothy D McHugh, Giuseppe Ippolito, Giovanni Battista Migliori, Markus J Maeurer, Alimuddin Zumla
Tuberculosis remains the world's leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016-of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens...
March 23, 2018: Lancet Infectious Diseases
Simon Tiberi, Andrea Maurizio Cabibbe, Jennifer Tomlins, Daniela Maria Cirillo, Giovanni Battista Migliori
No abstract text is available yet for this article.
March 2018: EBioMedicine
Tiziana Masini, Janika Hauser, Rutendo Kuwana, Nguyen Nhat Linh, Ernesto Jaramillo
No abstract text is available yet for this article.
March 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
V Cox, G Brigden, R H Crespo, E Lessem, S Lynch, M L Rich, B Waning, J Furin
SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens. DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017...
April 1, 2018: International Journal of Tuberculosis and Lung Disease
André Campaniço, Rui Moreira, Francisca Lopes
Tuberculosis (TB) remains a major health problem worldwide. The infectious agent, Mycobacterium tuberculosis, has a unique ability to survive within the host, alternating between active and latent disease states, and escaping the immune system defences. The extended duration of anti-TB regimens and the increasing prevalence of multidrug- (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have created an urgent need for new antibiotics active against drug-resistant organisms and that can shorten standard therapy...
March 9, 2018: European Journal of Medicinal Chemistry
Cheon Tae Kim, Tae-Ok Kim, Hong-Joon Shin, Young Chun Ko, Yeong Hun Choe, Hak-Ryul Kim, Yong-Soo Kwon
Relatively little is known about the efficacy and safety of the programmatic use of bedaquiline and delamanid in multidrug-resistant tuberculosis (MDR-TB) treatment.This study evaluated 61 patients with MDR-TB treated with bedaquiline (n=39), delamanid (n=11) or both, either sequentially (n=10) or in coadministration (n=1), for >1 month, combined with a World Health Organization-recommended regimen.Of these, 49 (80.3%) were male and 12 (19.7%) were female. The median (interquartile range (IQR)) age was 53 (38...
March 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Sebastian Polak, Klaus Romero, Alexander Berg, Nikunjkumar Patel, Masoud Jamei, David Hermann, Debra Hanna
Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk...
June 2018: Journal of Pharmacokinetics and Pharmacodynamics
Kiel Hards, Gregory M Cook
From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted "one-size fits all" approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics...
January 2018: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
S Tiberi, M Muñoz-Torrico, R Duarte, M Dalcolmo, L D'Ambrosio, G-B Migliori
Tuberculosis (TB) is the ninth cause of global death, more than any other infectious disease. With growing drug resistance the epidemic remains and will require significant attention and investment for the elimination of this disease to occur. With susceptible TB treatment not changing over the last four decades and the advent of drug resistance, new drugs and regimens are required. Recently, through greater collaboration and research networks some progress with significant advances has taken place, not withstanding the comparatively low amount of resources invested...
March 2018: Pulmonology
Hamish S Sutherland, Amy S T Tong, Peter J Choi, Daniel Conole, Adrian Blaser, Scott G Franzblau, Christopher B Cooper, Anna M Upton, Manisha U Lotlikar, William A Denny, Brian D Palmer
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90 s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these...
May 1, 2018: Bioorganic & Medicinal Chemistry
Iram Khan Iqbal, Sapna Bajeli, Ajit Kumar Akela, Ashwani Kumar
Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents...
February 23, 2018: Pathogens
A Van Deun, T Decroo, A Piubello, B C de Jong, L Lynen, H L Rieder
Current World Health Organization guidelines for the formulation of treatment regimens for multidrug-resistant tuberculosis (MDR-TB) pay too little attention to the microbiological activity of anti-tuberculosis drugs. Here, we draw lessons from the pioneering work done on shorter MDR-TB treatment regimens and the current knowledge of the bactericidal and sterilizing properties of the drugs to inform the composition of treatment regimens for MDR-TB. We propose to reserve the term 'core drug' for the one drug in a regimen that contributes most to relapse-free cure...
March 1, 2018: International Journal of Tuberculosis and Lung Disease
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