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https://www.readbyqxmd.com/read/28937657/synthesis-of-2-4-diaminopyrimidine-core-based-derivatives-and-biological-evaluation-of-their-anti-tubercular-activities
#1
Yifan Ouyang, Hao Yang, Peng Zhang, Yu Wang, Sargit Kaur, Xuanli Zhu, Zhe Wang, Yutong Sun, Wei Hong, Yun Fong Ngeow, Hao Wang
Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level...
September 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28935918/host-directed-therapies-for-bacterial-and-viral-infections
#2
REVIEW
Stefan H E Kaufmann, Anca Dorhoi, Richard S Hotchkiss, Ralf Bartenschlager
Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology...
September 22, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28934901/association-of-ugt2b7-polymorphisms-with-risk-of-induced-liver-injury-by-anti-tuberculosis-drugs-in-chinese-han
#3
Guo Chen, Shou-Quan Wu, Mei Feng, Yu Wang, Jing-Can Wu, Gui-Yi Ji, Miao-Miao Zhang, Qian-Qian Liu, Jian-Qing He
Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform...
September 1, 2017: International Journal of Immunopathology and Pharmacology
https://www.readbyqxmd.com/read/28933243/drug-targets-in-dormant-mycobacterium-tuberculosis-can-the-conquest-against-tuberculosis-become-a-reality
#4
Vivek Kumar Gupta, M Madhan Kumar, Dharmendra Singh, Deepa Bisht, Shweta Sharma
Targeting M. tuberculosis (Mtb) in latent form of infection is a major obstacle and big challenge in tuberculosis (TB) eradication by current chemotherapy. A better understanding of the physiology of Mtb and of the metabolic state of the bacillus during the dormancy, is a primary need in finding drug targets against non replicating persistent (NRP) form of the Mtb. Identification of potential drug targets against dormant state of Mtb is critically important to achieve the goal of complete eradication for shortening of anti-TB therapy...
September 21, 2017: Infectious Diseases
https://www.readbyqxmd.com/read/28932979/tuberculous-meningitis-in-children-and-adults-new-insights-for-an-ancient-foe
#5
REVIEW
Alyssa Mezochow, Kiran Thakur, Christopher Vinnard
PURPOSE OF REVIEW: Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science. RECENT FINDINGS: Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids...
September 20, 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28928173/cohort-profile-of-a-study-on-outcomes-related-to-tuberculosis-and-antiretroviral-drug-concentrations-in-uganda-design-methods-and-patient-characteristics-of-the-south-study
#6
Christine Sekaggya-Wiltshire, Barbara Castelnuovo, Amrei von Braun, Joseph Musaazi, Daniel Muller, Allan Buzibye, Ursula Gutteck, Lars Henning, Bruno Ledergerber, Natascia Corti, Mohammed Lamorde, Jan Fehr, Andrew Kambugu
PURPOSE: Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. PARTICIPANTS: Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on first-line anti-TB treatment...
September 18, 2017: BMJ Open
https://www.readbyqxmd.com/read/28927812/bi-pssm-position-specific-scoring-matrix-based-intelligent-computational-model-for-identification-of-mycobacterial-membrane-proteins
#7
Muslim Khan, Maqsood Hayat, Sher Afzal Khan, Saeed Ahmad, Nadeem Iqbal
Mycobacterium is a pathogenic bacterium, which is a causative agent of tuberculosis (TB) and leprosy. These diseases are very crucial and become the cause of death of millions of people every year in the world. So, the characterize structure of membrane proteins of the protozoan play a vital role in the field of drug discovery because, without any knowledge about this Mycobacterium's membrane protein and their types, the scientists are unable to treat this pathogenic protozoan. So, an accurate and competitive computational model is needed to characterize this uncharacterized structure of mycobacterium...
September 16, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28927024/in-vitro-activities-of-enantiopure-and-racemic-1-acetoxychavicol-acetate-against-clinical-isolates-of-mycobacterium-tuberculosis
#8
Saradee Warit, Kamolchanok Rukseree, Therdsak Prammananan, Poonpilas Hongmanee, Pamaree Billamas, Sarinya Jaitrong, Angkana Chaiprasert, Birgit U Jaki, Guido F Pauli, Scott G Franzblau, Prasit Palittapongarnpim
In the process of evaluating the effect of several plant extracts against Mycobacterium tuberculosis using the Microplate Alamar Blue Assay (MABA), an extract of Thai herb Alpinia galanga rhizome and its major component, 1'-acetoxychavicol acetate (ACA), exhibited marked anti-tuberculosis activity. The minimal inhibition concentrations (MICs) of the S-enantiomer of ACA (S-ACA) against M. tuberculosis H37Ra ATCC 25177 and H37Rv ATCC 27294 strains were 0.2 µg/mL and 0.7 µg/mL, respectively. More than 95% of 100 drug-sensitive and 50 drug-resistant mycobacterial clinical isolates were inhibited by extracted S-ACA at 1...
September 18, 2017: Scientia Pharmaceutica
https://www.readbyqxmd.com/read/28919150/in-vitro-anti-tuberculosis-activity-of-azole-drugs-against-mycobacterium-tuberculosis-clinical-isolates
#9
Belén R Imperiale, Ángel A Cataldi, Nora S Morcillo
BACKGROUND: Latent tuberculosis has been associated with the persistence of dormant Mycobacterium tuberculosis in the organism of infected individuals, who are reservoirs of the bacilli and the source for spreading the disease in the community. New active anti-TB drugs exerting their metabolic action at different stages and on latent/dormant bacilli are urgently required to avoid endogenous reactivations and to be part of treatments of multi- and extensively-drug resistant tuberculosis (M/XDR-TB)...
September 14, 2017: Revista Argentina de Microbiología
https://www.readbyqxmd.com/read/28917089/the-trehalose-specific-transporter-lpqy-sugabc-is-required-for-antimicrobial-and-anti-biofilm-activity-of-trehalose-analogues-in-mycobacterium-smegmatis
#10
Jeffrey M Wolber, Bailey L Urbanek, Lisa M Meints, Brent F Piligian, Irene C Lopez-Casillas, Kailey M Zochowski, Peter J Woodruff, Benjamin M Swarts
Mycobacteria, including the bacterial pathogen that causes human tuberculosis, possess distinctive pathways for synthesizing and utilizing the non-mammalian disaccharide trehalose. Trehalose metabolism is essential for mycobacterial viability and has been linked to in vitro biofilm formation, which may bear relevance to in vivo drug tolerance. Previous research has shown that some trehalose analogues bearing modifications at the 6-position inhibit growth of various mycobacterial species. In this work, 2-, 5-, and 6-position-modified trehalose analogues were synthesized using our previously reported one-step chemoenzymatic method and shown to inhibit growth and biofilm formation in the two-to three-digit micromolar range in Mycobacterium smegmatis...
August 9, 2017: Carbohydrate Research
https://www.readbyqxmd.com/read/28914808/structural-and-dynamics-perspectives-on-the-binding-of-substrate-and-inhibitors-in-mycobacterium-tuberculosis-dhfr
#11
Pimonluck Sittikornpaiboon, Pisanu Toochinda, Luckhana Lawtrakul
Dihydrofolate reductase (DHFR), an essential enzyme in the folate pathway, is a potential target for new anti-tuberculosis drugs. Fifteen crystal structures of Mycobacterium tuberculosis DHFR complexed with NADPH and various inhibitors are available in the RCSB Protein Data Bank, but none of them is a substrate binding structure. Therefore, we performed molecular dynamics simulations on ternary complexes of M. tuberculosis DHFR:NADPH with a substrate (dihydrofolate) and each of three competitive inhibitors the in 2,4-diaminopyrimidine series (P1, P157, and P169), in order to gain insight into the inhibition-mechanism of DHFR in the folate pathway...
September 15, 2017: Scientia Pharmaceutica
https://www.readbyqxmd.com/read/28911362/assessment-of-the-quality-of-anti-tuberculosis-medicines-in-almaty-kazakhstan-2014
#12
D Nabirova, G Schmid, R Yusupova, M Kantarbayeva, S I Ismailov, D Moffett, R W O Jähnke, J P Nuorti
SETTING: In 2009, the World Health Organization (WHO) conducted a survey of the quality of four anti-tuberculosis drugs in the former Soviet Union countries. Kazakhstan had the highest proportion of substandard drugs. OBJECTIVE: To assess the quality of anti-tuberculosis drugs used in Kazakhstan in 2014. DESIGN: Fourteen anti-tuberculosis drugs from the Almaty Interdistrict TB Dispensary were randomly selected and screened for quality using Global Pharma Health Fund Minilab™ testing...
October 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28911359/interferon-gamma-response-to-the-treatment-of-active-pulmonary-and-extra-pulmonary-tuberculosis
#13
L Liang, R Shi, X Liu, X Yuan, S Zheng, G Zhang, W Wang, J Wang, K England, L E Via, Y Cai, L C Goldfeder, L E Dodd, C E Barry, R Y Chen
BACKGROUND: Interferon-gamma (IFN-γ) release assays (IGRAs) are used to diagnose tuberculosis (TB) but not to measure treatment response. OBJECTIVE: To measure IFN-γ response to active anti-tuberculosis treatment. DESIGN: Patients from the Henan Provincial Chest Hospital, Henan, China, with TB symptoms and/or signs were enrolled into this prospective, observational cohort study and followed for 6 months of treatment, with blood and sputum samples collected at 0, 2, 4, 6, 8, 16 and 24 weeks...
October 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28900877/genetic-polymorphisms-of-slco1b1-cyp2e1-and-ugt1a1-and-susceptibility-to-anti-tuberculosis-drug-induced-hepatotoxicity-a-chinese-population-based-prospective-case-control-study
#14
Qin Sun, Hai-Peng Liu, Rui-Juan Zheng, Peng Wang, Zhi-Bin Liu, Wei Sha, He-Ping Xiao
BACKGROUND: Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH). METHODS: Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case-control study...
September 12, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28892927/a-rare-instance-of-levofloxacin-induced-myoclonus
#15
Sushil Kiran Kunder, A Avinash, Veena Nayak, Amod Tilak
Levofloxacin is a widely used fluoroquinolone, mainly as a respiratory antimicrobial agent. It is employed as a second line therapeutic modality in pulmonary tuberculosis as well. The drug has been in use for ages, and is known to be both efficacious and safe. However, it is not free of adverse effects. The most dangerous ones are those involving the Central Nervous System (CNS). Although rare, levofloxacin can cause involuntary movements like chorea and myoclonus. Here by, we present a case of an elderly male patient who developed reversible myoclonus/chorea after a course of levofloxacin (which was initiated as part of his anti-tubercular therapy) following the development of peripheral neuropathy secondary to isoniazid...
July 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28892605/inhibitors-of-the-diadenosine-tetraphosphate-phosphorylase-rv2613c-of-mycobacterium-tuberculosis
#16
Kathrin H Götz, Stephan M Hacker, Daniel Mayer, Jan-Niklas Dürig, Steffen Stenger, Andreas Marx
The intracellular concentration of diadenosine tetraphospate (Ap4A) rises upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response, remains to be discovered. As the turnover of Ap4A by Ap4A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap4A...
September 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28887289/baseline-resistance-and-cross-resistance-among-fluoroquinolones-in-multi-drug-resistant-mycobacterium-tuberculosis-isolates-at-a-national-reference-laboratory
#17
Mamatha H G, V Shanthi
OBJECTIVES: Pre-existing fluoroquinolone (FQ) resistance in Multiple Drug Resistant Tuberculosis (MDR TB) patients is a major threat in treating MDR TB. This study was conducted to assess the percentage of FQ resistance among MDR TB patients and to determine whether there is complete cross-resistance between FQs (ofloxacin, levofloxacin and moxifloxacin) used as second line drugs in TB treatment. METHODS: Among 879 MDR TB suspects tested, 68 were confirmed to be MDRTB and mono rifampicin resistant...
September 5, 2017: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/28884751/tuberculous-meningitis
#18
REVIEW
Robert J Wilkinson, Ursula Rohlwink, Usha Kant Misra, Reinout van Crevel, Nguyen Thi Hoang Mai, Kelly E Dooley, Maxine Caws, Anthony Figaji, Rada Savic, Regan Solomons, Guy E Thwaites
Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation...
September 8, 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/28879439/mannose-binding-lectin-mbl-deficiency-and-tuberculosis-infection-in-patients-with-ankylosing-spondylitis
#19
Renato Nisihara, Thelma Skare, Vinícius Maestri, Juliana S Alegretti, Ana Paula B Campos, Iara Messias-Reason
Ankylosing spondylitis (AS) patients may have higher prevalence of mannose-binding lectin (MBL) deficiency than normal individuals. MBL deficiency may influence susceptibility to infections. The aim of the study was to verify if MBL deficiency in patients with AS predisposes to infections. We studied 60 patients with AS diagnosed according to the Assessment of SpondyloArthritis international Society (ASAS) criteria. These patients had their MBL serum levels determinated. Twenty-five individuals were identified as MBL deficient (serum values 100 ng/mL)...
September 6, 2017: Clinical Rheumatology
https://www.readbyqxmd.com/read/28879159/molecular-characterisation-of-rifampicin-resistant-mycobacterium-tuberculosis-strains-from-malawi
#20
Tarsizio Chikaonda, Irene Ketseoglou, Nelson Nguluwe, Robert Krysiak, Isaac Thengolose, Felix Nyakwawa, Nora E Rosenberg, Christopher Stanley, James Mpunga, Irving F Hoffman, Maria A Papathanasopoulos, Mina Hosseinipour, Lesley Scott, Wendy Stevens
BACKGROUND: Availability and access to the detection of resistance to anti-tuberculosis drugs remains a significant challenge in Malawi due to limited diagnostic services. The Xpert(®) MTB/RIF can detect Mycobacterium tuberculosis and resistance to rifampicin in a single, rapid assay. Rifampicin-resistant M. tuberculosis has not been well studied in Malawi. OBJECTIVES: We aimed to determine mutations in the rifampicin resistance determining region (RRDR) of the rpoB gene of M...
2017: African Journal of Laboratory Medicine
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