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https://www.readbyqxmd.com/read/28075132/discovery-of-imidazo-1-2-a-pyridine-ethers-and-squaramides-as-selective-and-potent-inhibitors-of-mycobacterial-adenosine-triphosphate-atp-synthesis
#1
Subramanyam J Tantry, Shankar D Markad, Vikas Shinde, Jyothi Bhat, Gayathri Balakrishnan, Amit K Gupta, Anisha Ambady, Anandkumar V Raichurkar, Chaitanyakumar Kedari, Sreevalli Sharma, Naina V Mudugal, Ashwini Narayan, C N Naveen Kumar, Robert Nanduri, Sowmya Bharath, Jitendar Reddy, Vijender Panduga, Prabhakar K R, Karthikeyan Kandaswamy, Ramanatha Saralaya, Parvinder Kaur, Neela Dinesh, Supreeth Guptha, Kirsty Rich, David Murray, Helen Plant, Marian Preston, Helen Ashton, Darren Plant, Jarrod Walsh, Peter Alcock, Kathryn Naylor, Matthew Collier, James Whiteaker, Robert E McLaughlin, Meenakshi Mallya, Manoranjan Panda, Suresh Rudrapatna, Vasanthi Ramachandran, Radha K Shandil, Vasan K Sambandamurthy, Khisimuzi Mdluli, Christopher B Cooper, Harvey Rubin, Takahiro Yano, Pravin S Iyer, Shridhar Narayanan, Stefan Kavanagh, Kakoli Mukherjee, V Balasubramanian, Vinayak P Hosagrahara, Suresh Solapure, Sudha Ravishankar, Shahul Hameed P
The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis. Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP-synthesis. Through medicinal chemistry exploration, we established a robust structure activity relationship of these two scaffolds resulting in nanomolar potencies in an ATP-synthesis inhibition assay...
January 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28073970/estimated-generic-prices-for-novel-treatments-for-drug-resistant-tuberculosis
#2
Dzintars Gotham, Joseph Fortunak, Anton Pozniak, Saye Khoo, Graham Cooke, Frederick E Nytko, Andrew Hill
BACKGROUND: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course. OBJECTIVES: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture. METHODS: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API)...
January 10, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28043638/activity-of-drugs-against-dormant-mycobacterium-tuberculosis
#3
A Iacobino, G Piccaro, F Giannoni, A Mustazzolu, L Fattorini
OBJECTIVE/BACKGROUND: Heterogeneous mixtures of cellular and caseous granulomas coexist in the lungs of tuberculosis (TB) patients, with Mycobacterium tuberculosis (Mtb) existing from actively replicating (AR) to dormant, nonreplicating (NR) stages. Within cellular granulomas, the pH is estimated to be less than 6, whereas in the necrotic centres of hypoxic, cholesterol/triacylglycerol-rich, caseous granulomas, the pH varies between 7.2 and 7.4. To combat TB, we should kill both AR and NR stages of Mtb...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28043617/bedaquiline-in-the-multidrug-resistant-tuberculosis-treatment-belarus-experience
#4
Alena Skrahina, Hennadz Hurevich, Dennis Falzon, Liudmila Zhilevich, Valiantsin Rusovich, Masoud Dara, Svetlana Setkina
BACKGROUND/OBJECTIVE: Outcomes of treatment for multidrug-resistant tuberculosis (MDR-TB) remain poor worldwide. Among patients with MDR-TB in Belarus who started treatment in 2012, only 54% completed it successfully, with treatment failure reported in 22% of the patients; additionally, 11% died and 13% were lost to follow-up or remained unevaluated. In Belarus, to improve outcomes, bedaquiline was introduced in MDR-TB treatment in June 2015. The national TB program developed measures to monitor safety and effectiveness of bedaquiline-containing regimens in line with the World Health Organization recommendations...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28043603/individualized-treatment-of-multidrug-resistant-tuberculosis-using-therapeutic-drug-monitoring
#5
Mathieu S Bolhuis, Onno W Akkerman, Marieke G G Sturkenboom, Wiel C M de Lange, Tjip S van der Werf, Jan-Willem C Alffenaar
OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems with medication adherence. Pharmacokinetic variability is also attributed as one of the reasons contributing to treatment failure. In our reference Tuberculosis Center Beatrixoord (University Medical Center Groningen, Groningen, The Netherlands), we strive to individualize treatment of all MDR-TB patients based on drug-susceptibility testing using minimal inhibitory concentrations and pharmacokinetic parameters...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28043500/design-and-development-of-novel-inhibitors-for-the-treatment-of-latent-tuberculosis
#6
Rudraraju Srilakshmi Reshma, Perumal Yogeeswari, Dharmarajan Sriram
OBJECTIVE/BACKGROUND: "The captain of all these men of death", is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28038962/confirming-model-predicted-pharmacokinetic-interactions-between-bedaquiline-and-lopinavir-ritonavir-or-nevirapine-in-patients-with-hiv-and-drug-resistant-tuberculosis
#7
Margreke J E Brill, Elin M Svensson, Mishal Pandie, Gary Maartens, Mats O Karlsson
Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14)...
December 14, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28031270/unexpected-high-prevalence-of-resistance-associated-rv0678-variants-in-mdr-tb-patients-without-documented-prior-use-of-clofazimine-or-bedaquiline
#8
Cristina Villellas, Nele Coeck, Conor J Meehan, Nacer Lounis, Bouke de Jong, Leen Rigouts, Koen Andries
OBJECTIVES: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. METHODS: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar...
December 28, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27999020/spectinamides-are-effective-partner-agents-for-the-treatment-of-tuberculosis-in-multiple-mouse-infection-models
#9
Gregory T Robertson, Michael S Scherman, David F Bruhn, Jiuyu Liu, Courtney Hastings, Michael R McNeil, Michelle M Butler, Terry L Bowlin, Robin B Lee, Richard E Lee, Anne J Lenaerts
OBJECTIVES: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents...
December 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27994440/use-of-bedaquiline-and-delamanid-in-diabetes-patients-clinical-and-pharmacological-considerations
#10
REVIEW
Minhui Hu, Chunlan Zheng, Feng Gao
Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo(®) (bedaquiline) and Deltyba(®) (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27993848/mycobacterium-tuberculosis-is-selectively-killed-by-rifampin-and-rifapentine-in-hypoxia-at-neutral-ph
#11
Angelo Iacobino, Giovanni Piccaro, Federico Giannoni, Alessandro Mustazzolu, Lanfranco Fattorini
The activity of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine and pyrazinamide was tested against nonreplicating (dormant) Mycobacterium tuberculosis under conditions of hypoxia at pH 5.8 and 7.3 mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli while all other drugs showed little activity...
December 19, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27971538/cost-effectiveness-of-adding-bedaquiline-to-background-drug-regimens-for-the-treatment-of-multidrug-resistant-and-extensively-resistant-tuberculosis-in-italy
#12
L R Codecasa, M Toumi, A D'Ausilio, A Aiello, F Da Mele, R Termini, A Uglietti, R Hettle, G Graziano, S De Lorenzo
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27927925/the-emergence-of-mmpt5-variants-during-bedaquiline-treatment-of-mycobacterium-intracellulare-lung-disease
#13
David C Alexander, Ravikiran Vasireddy, Sruthi Vasireddy, Julie V Philley, Barbara A Brown-Elliott, Benjamin Perry, David E Griffith, Jeana L Benwill, Andrew D S Cameron, Richard J Wallace
Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for treatment of Mycobacterium tuberculosis (MTB) infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of thirteen patients with Mycobacterium intracellulare lung disease had an initial microbiological response, then relapsed. Whole genome comparison of pre-treatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5 Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in MTB...
December 7, 2016: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/27906009/current-trends-and-intricacies-in-the-management-of-hiv-associated-pulmonary-tuberculosis
#14
REVIEW
Narendran Gopalan, Padmapriyadarsini Chandrasekaran, Soumya Swaminathan, Srikanth Tripathy
Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary TB assumes utmost significance in the programmatic perspective as it is readily transmissible as well as easily diagnosable. HIV complicates every aspect of pulmonary tuberculosis from diagnosis to treatment, demanding a different approach to effectively tackle both the diseases. In order to control these converging epidemics, it is important to diagnose early, initiate appropriate therapy for both infections, prevent transmission and administer preventive therapy...
September 26, 2016: AIDS Research and Therapy
https://www.readbyqxmd.com/read/27878107/imaging-the-nadh-nad-homeostasis-for-understanding-the-metabolic-response-of-mycobacterium-to-physiologically-relevant-stresses
#15
Shabir A Bhat, Iram K Iqbal, Ashwani Kumar
The NADH:NAD(+) ratio is the primary indicator of the metabolic state of bacteria. NAD(H) homeostasis is critical for Mycobacterium tuberculosis (Mtb) survival and is thus considered an important drug target, but the spatio-temporal measurements of NAD(H) remain a challenge. Genetically encoded fluorescent biosensors of the NADH:NAD(+) ratios were recently described, paving the way for investigations of the metabolic state of pathogens during infection. Here we have adapted the genetically encoded biosensor Peredox for measurement of the metabolic state of Mtb in vitro and during infection of macrophage cells...
2016: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/27872065/in-vitro-susceptibility-testing-of-bedaquiline-against-mycobacterium-avium-complex
#16
Barbara A Brown-Elliott, Julie V Philley, David E Griffith, Foram Thakkar, Richard J Wallace
We performed bedaquiline broth microdilution susceptibilities using Clinical Laboratory Standards Institute (CLSI) guidelines on 103 respiratory isolates of Mycobacterium avium complex (MAC), including multidrug resistant isolates. Approximately 90% of isolates had bedaquiline minimal inhibitory concentrations (MICs) ≤0.008 μg/mL and 102/103 isolates had MICs ≤0.015 μg/mL. Bedaquiline has excellent potential for use in patients with MAC, although for reasons of its metabolism by the cytochrome P450 system, it should not be given with rifampin...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27865232/bedaquiline-introducing-a-new-drug-to-the-mdr-tb-armamentarium
#17
EDITORIAL
Chrispin Kambili
No abstract text is available yet for this article.
July 2016: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/27863179/population-pharmacokinetics-of-bedaquiline-and-metabolite-m2-in-patients-with-drug-resistant-tuberculosis-the-effect-of-time-varying-weight-and-albumin
#18
E M Svensson, A-G Dosne, M O Karlsson
Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time...
December 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27861363/efficacy-safety-and-tolerability-of-a-24-month-treatment-regimen-including-delamanid-in-a-child-with-extensively-drug-resistant-tuberculosis-a-case-report-and-review-of-the-literature
#19
Susanna Esposito, Samantha Bosis, Marina Tadolini, Sonia Bianchini, Giovanni Battista Migliori, Nicola Principi
RATIONAL: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are emerging problems in several countries. These infections require long and expensive treatment regimens. Recently, 2 new drugs, bedaquiline and delamanid, have been approved in several countries for use in adults with severe, difficult-to-treat MDR-TB, and it has been suggested that they could also be administered to children with MDR-TB and limited treatment options. However, no study has been completed on their efficacy...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27854508/new-repurposed-drugs-for-pediatric-multidrug-resistant-tuberculosis-practice-based-recommendations
#20
Elizabeth P Harausz, Anthony J Garcia-Prats, James A Seddon, H Simon Schaaf, Anneke C Hesseling, Jay Achar, Jonathan Bernheimer, Andrea Cruz, Lia D'Ambrosio, Anne Detjen, Stephen M Graham, Jennifer Hughes, Sylvie Jonckheere, Ben J Marais, Giovanni Battista Migliori, Lindsay McKenna, Alena Skrahina, Marina Tadolini, Peyton Wilson, Jennifer Furin
It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents...
November 17, 2016: American Journal of Respiratory and Critical Care Medicine
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