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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 co-administration (n=1), for more than 1 month, combined with a World Health Organization-recommended regimen. Of these, 49 (80.3%) were men and 12 (19.7%) were women. The median age was 53 years (interquartile range [IQR]=38...
March 15, 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...
March 8, 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, A Zumla, G-B Migliori
Tuberculosis (TB) continues to cause more deaths worldwide than any other infectious disease. Even though global TB incidence has been decreasing for some time, the proportion of drug resistance is increasing, contributing to greater complexity, morbidity, mortality, and cost. Since the advent of rifampicin in the 1960s, and the implementation of the standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have changed the first line regimen. This regimen while effective, has a long duration and pill burden, which has received little investment and innovation...
February 24, 2018: Revista Portuguesa de Pneumologia
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...
February 20, 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
Emanuele Pontali, Dina Visca, Rosella Centis, Lia D'Ambrosio, Antonio Spanevello, Giovanni Battista Migliori
PURPOSE OF REVIEW: Multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB epidemics are key obstacles towards TB control and elimination. RECENT FINDINGS: Diagnosis of MDR/XDR-TB is difficult and requires several weeks. New diagnostic tools are being tested and proposed allowing for shorter time to diagnosis and reduced delays in starting an adequate treatment regimen. MDR/XDR-TB treatment strategies are currently on an evolving stage...
February 20, 2018: Current Opinion in Pulmonary Medicine
Chao Chen, Susana Gardete, Robert Sander Jansen, Annanya Shetty, Thomas Dick, Kyu Y Rhee, Véronique Dartois
Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb's efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil's synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Gabriella Ferlazzo, Erika Mohr, Chinmay Laxmeshwar, Catherine Hewison, Jennifer Hughes, Sylvie Jonckheere, Naira Khachatryan, Virginia De Avezedo, Lusine Egazaryan, Amir Shroufi, Stobdan Kalon, Helen Cox, Jennifer Furin, Petros Isaakidis
BACKGROUND: Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa...
February 13, 2018: Lancet Infectious Diseases
Marina Tadolini, Simon Tiberi, Giovanni Battista Migliori
No abstract text is available yet for this article.
February 13, 2018: Lancet Infectious Diseases
J Cory Kalvass, Colin Phipps, Gary J Jenkins, Patricia Stuart, Xiaomei Zhang, Lance Heinle, Marjoleen J M A Nijsen, Volker Fischer
A flux dialysis method to measure unbound fraction ( f u ) of compounds with high protein binding and other challenging properties was tested and validated. This method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of the compound initial concentration, f u , and unbound dialysis membrane permeability ( P mem ). Therefore, f u can be determined from the initial concentration and flux rate, assuming membrane P mem is known...
April 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Samantha Wellington, Deborah T Hung
After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy...
February 15, 2018: ACS Infectious Diseases
Catherine Vilchèze, Brian Weinrick, Lawrence W Leung, William R Jacobs
Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline...
January 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shin Joon, Ragunathan Priya, Sundararaman Lavanya, Wilson Nartey, Subhashri Kundu, Malathy Sony Subramanian Manimekalai, Nebojša Bogdanović, Thomas Dick, Gerhard Grüber
Mycobacterium tuberculosis (Mt) F1 FO ATP synthase (α3 :β3 :γ:δ:ε:a:b:b':c9 ) is essential for the viability of growing and non-growing persister cells of the pathogen. Here we present the first NMR solution structure of Mtε, revealing an N-terminal β-barrel domain (NTD) and a C-terminal domain (CTD) composed of a helix-loop-helix with helix 1 and -2 being shorter compared to their counterparts in other bacteria. The C-terminal amino acids are oriented towards the NTD, forming a domain-domain interface between the NTD and CTD...
January 23, 2018: FEBS Journal
Leah Lande, Jason George, Theodore Plush
PURPOSE OF REVIEW: The prevalence of Mycobacterium avium complex (MAC)-related pulmonary disease has been increasing because of environmental factors, changes in organism virulence, and evolving host susceptibility. Treatment is often complicated by adverse effects, development of drug resistance, and refractory disease, with recurrence rates as high as 25-45%. RECENT FINDINGS: Aerosolization of water, soil, or dusts are the likely sources of MAC-related pulmonary disease in susceptible individuals...
April 2018: Current Opinion in Infectious Diseases
Nazir A Ismail, Shaheed V Omar, Lavania Joseph, Netricia Govender, Linsay Blows, Farzana Ismail, Hendrik Koornhof, Andries W Dreyer, Koné Kaniga, Norbert Ndjeka
BACKGROUND: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ). METHODS: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960...
January 9, 2018: EBioMedicine
V Cox, J Furin
The World Health Organization uses a Grading of Recommendations Assessment, Development, and Evaluation process to make recommendations for treating multidrug-resistant tuberculosis. Even with this standardized approach, there have been discrepancies between recommendations for newer drugs such as bedaquiline and delamanid and the shorter regimen. This may be because newer drugs are novel chemical entities and may merit closer scrutiny. Here, we explore the problematic nature of this supposition, arguing that although the newer drugs have been used in fewer individuals, they may have more robust efficacy and safety data than many of the second-line drugs used in the shorter regimen...
December 1, 2017: International Journal of Tuberculosis and Lung Disease
Kit Ieng Kuok, Phoebe Choi In Ng, Xia Ji, Chunming Wang, Wing Wai Yew, Denise P C Chan, Jun Zheng, Simon M Y Lee, Ruibing Wang
Bedaquiline (BDQ) is a newly approved anti-tuberculosis drug in treating multidrug-resistant tuberculosis. However, it has very poor aqueous solubility and several case reports have proposed that BDQ has potential risk of cardiotoxicity to patients. In this present study, we have explored into employing host-guest interactions between a synthetic receptor, cucurbit[7]uril (CB[7]), and BDQ aiming to improve the solubility and reduce the inherent cardiotoxicity of BDQ. HPLC-UV test on the solubility of BDQ in the absence and in the presence of increasing concentrations of CB[7] suggested a host-dependent guest-solubility enhancements...
December 16, 2017: Food and Chemical Toxicology
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