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Rupesh Vitthalrao Chikhale, Mahesh A Barmade, Prashant R Murumkar, Mange Ram Yadav
Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium...
May 31, 2018: Journal of Medicinal Chemistry
Lu Xiong, Chao Gao, Yao-Jie Shi, Xin Tao, Cui-Ting Peng, Juan Rong, Kun-Lin Liu, Qian Lei, Yi-Wen Zhang, Ning-Yu Wang, Luo-Ting Yu
Tuberculosis (TB) is a major global health problem, and the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-D-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Herein, the metabolites of the new DprE1 inhibitor SKLB-TB1001 in vivo and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) in vitro were studied...
April 23, 2018: Antimicrobial Agents and Chemotherapy
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...
April 25, 2018: European Journal of Medicinal Chemistry
Gang Zhang, Song Guo, Huaqing Cui, Jianguo Qi
Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package...
February 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jineetkumar Gawad, Chandrakant Bonde
Tuberculosis (TB) is the major threat for humans from past several decades. Even after advent of several antitubercular drugs, researchers are still struggling for the mycobacterial infections in humans are TB and leprosy. Chronic infections caused by Mycobacterium tuberculosis and Mycobacterium leprae. A particular problem with both of these organisms is that they can survive inside macrophages after phagocytosis, unless these cells are activated by cytokines produced by T-lymphocytes, because of this researchers are not yet succeeded in finding effective treatment on TB...
January 2018: Indian Journal of Tuberculosis
Rafal Sawicki, Elwira Sieniawska, Marta Swatko-Ossor, Joanna Golus, Grazyna Ginalska
In the past few years, there has been a significant increase in detection of drug resistant strains of Mycobacterium tuberculosis. Search for new antimycobacterial drugs brought natural sources with their chemical diversity in focus. Especially essential oils, produced by plants also for toxic effect, are reservoir of potentially antitubercular compounds. In the present work, we exposed M. tuberculosis H37Ra ATCC 25177 strain to some terpenes commonly occurring in essential oils. Gene expression profiling was used to explore possible influence of these compounds on stress sensing and envelope preserving function...
February 2018: Food and Chemical Toxicology
Francesca Boldrin, Giulia Degiacomi, Agnese Serafini, Gaëlle S Kolly, Marcello Ventura, Claudia Sala, Roberta Provvedi, Giorgio Palù, Stewart T Cole, Riccardo Manganelli
A range of regulated gene expression systems has been developed for mycobacteria in the last few years to facilitate the study of essential genes, validate novel drug targets and evaluate their vulnerability. Among these, the TetR/Pip-OFF repressible promoter system was successfully used in several mycobacterial species both in vitro and in vivo. In the first version of the system, the repressible promoter was Pptr , a strong Pip-repressible promoter of Streptomyces pristinaespiralis, which might hamper effective downregulation of genes with a low basal expression level...
January 2018: Microbial Biotechnology
Lucia Semelková, Petra Janošcová, Carlos Fernandes, Ghada Bouz, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Lucie Navrátilová, Jiří Kuneš, Martin Doležal, Jan Zitko
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity...
September 7, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Renhe Liu, Xiaoxuan Lyu, Sarah M Batt, Mei-Hui Hsu, Michael B Harbut, Catherine Vilchèze, Bo Cheng, Kehinde Ajayi, Baiyuan Yang, Yun Yang, Hui Guo, Changyou Lin, Fei Gan, Chen Wang, Scott G Franzblau, William R Jacobs, Gurdyal S Besra, Eric F Johnson, Mike Petrassi, Arnab K Chatterjee, Klaus Fütterer, Feng Wang
Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9...
October 9, 2017: Angewandte Chemie
Sumita Karan, Vipin K Kashyap, Syed Shafi, Ajay K Saxena
Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose oxidase (MtbDprE1) acts in concert with decaprenylphosphoryl-β-D-ribose 2-epimerase (MtbDprE2) and catalyzes the epimerization of DPR into DPA. DPA is the sole precursor for synthesis of arabinogalactan and lipoarabinomannan in the mycobacterial cell wall. MtbDprE1 is a unique antimalarial drug target and many covalent and non-covalent inhibitors against MtbDprE1 have been studied for their antituberculosis activities. In the current study, we have purified MtbDprE1 enzyme and synthesized six sulfur-rich 2-mercaptobenzothiazole and 1, 2, 3-triazole conjugated ligands and performed binding analysis with MtbDprE1...
August 2017: Journal of Molecular Modeling
Abdul Aziz Ali, Dhrubajyoti Gogoi, Amrita K Chaliha, Alak K Buragohain, Priyanka Trivedi, Prakash J Saikia, Praveen S Gehlot, Arvind Kumar, Vinita Chaturvedi, Diganta Sarma
A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular 'click chemistry' approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages)...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
Katarína Mikušová, Sean Ekins
Tuberculosis drug discovery has shifted in recent years from a primarily target-based approach to one that uses phenotypic high-throughput screens. As examples of this, through our EU-funded FP7 collaborations, New Medicines for Tuberculosis was target-based and our more-recent More Medicines for Tuberculosis project predominantly used phenotypic screening. From these projects we have examples of success (DprE1) and failure (PimA) going from drug to target and from target to drug, respectively. It is clear that we still have much to learn about the drug targets and the complex effects of the drugs on Mycobacterium tuberculosis...
March 2017: Drug Discovery Today
Jérémie Piton, Caroline S-Y Foo, Stewart T Cole
The flavoenzyme DprE1 catalyses a crucial step in arabinan production for cell wall biosynthesis in Mycobacterium tuberculosis and is a highly vulnerable drug target. It was first discovered using benzothiazinones (BTZ): exquisitely potent bactericidal agents that are being developed as drugs to treat tuberculosis. Subsequently, many compounds with diverse scaffolds were found to act as either covalent or noncovalent DprE1 inhibitors. Covalent inhibitors, like the BTZ, are all nitroaromatic compounds that serve as suicide substrates after DprE1-mediated nitroreduction...
March 2017: Drug Discovery Today
Sarah M Batt, Monica Cacho Izquierdo, Julia Castro Pichel, Christopher J Stubbs, Laura Vela-Glez Del Peral, Esther Pérez-Herrán, Neeraj Dhar, Bernadette Mouzon, Mike Rees, Jonathan P Hutchinson, Robert J Young, John D McKinney, David Barros Aguirre, Lluis Ballell, Gurdyal S Besra, Argyrides Argyrou
We have targeted the Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose oxidase (Mt-DprE1) for potential chemotherapeutic intervention of tuberculosis. A multicopy suppression strategy that overexpressed Mt-DprE1 in M. bovis BCG was used to profile the publically available GlaxoSmithKline antimycobacterial compound set, and one compound (GSK710) was identified that showed an 8-fold higher minimum inhibitory concentration relative to the control strain. Analogues of GSK710 show a clear relationship between whole cell potency and in vitro activity using an enzymatic assay employing recombinant Mt-DprE1, with binding affinity measured by fluorescence quenching of the flavin cofactor of the enzyme...
December 11, 2015: ACS Infectious Diseases
Pravin S Mahajan, Mukesh D Nikam, Laxman U Nawale, Vijay M Khedkar, Dhiman Sarkar, Charansingh H Gill
In vitro and ex vivo efficacies of four series of benzo[b]thiophene-2-carboxylic acid derivatives were studied against Mycobacterium tuberculosis H37Ra (MTB). Benzo[b]thiophenes were also tested in vitro against multidrug resistant Mycobacterium tuberculosis H37Ra (MDR-MTB), and 7b was found to be highly active against A- and D-MDR-MTB/MTB (MIC ranges 2.73-22.86 μg/mL). The activity of all benzo[b]thiophenes against M. bovis BCG (BCG) was also assessed grown under aerobic and under conditions of oxygen depletion...
August 11, 2016: ACS Medicinal Chemistry Letters
Caroline Shi-Yan Foo, Benoit Lechartier, Gaëlle S Kolly, Stefanie Boy-Röttger, João Neres, Jan Rybniker, Andréanne Lupien, Claudia Sala, Jérémie Piton, Stewart T Cole
Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position into dprE1 of M...
November 2016: Antimicrobial Agents and Chemotherapy
Thulasi Warrier, Kanishk Kapilashrami, Argyrides Argyrou, Thomas R Ioerger, David Little, Kenan C Murphy, Madhumitha Nandakumar, Suna Park, Ben Gold, Jianjie Mi, Tuo Zhang, Eugenia Meiler, Mike Rees, Selin Somersan-Karakaya, Esther Porras-De Francisco, Maria Martinez-Hoyos, Kristin Burns-Huang, Julia Roberts, Yan Ling, Kyu Y Rhee, Alfonso Mendoza-Losana, Minkui Luo, Carl F Nathan
The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Chao Gao, Cuiting Peng, Yaojie Shi, Xinyu You, Kai Ran, Lu Xiong, Ting-Hong Ye, Lidan Zhang, Ningyu Wang, Yongxia Zhu, Kun Liu, Weiqiong Zuo, Luoting Yu, Yuquan Wei
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates...
2016: Scientific Reports
Martin Krátký, Jarmila Vinsova
The global tuberculosis epidemic and emergence of drug resistance call for intensive research on new antimycobacterial agents. Recent development is focused mainly on heterocyclic molecules. In many cases, introduction of sulphur has improved antimicrobial activity; many drugs feature a sulphur heterocycle. Thiophene derivatives and thiadiazoles including derived ortho-condensed heterocycles have been found to have a wide range of biological activities. This review highlights the recent progress in the field with a focus on whole-cell antimycobacterial activity of the agents as well as targeting of enzymes from Mycobacterium tuberculosis...
2016: Current Topics in Medicinal Chemistry
Richa Anand
Tuberculosis is the most prominent contagious disease and needs the new targets and drugs identification. Target identification and validation is a crucial step in drug discovery process. In Mycobacterium tuberculosis, decaprenyl-phosphoryl-β-D-ribose 2'-oxidase is a potential target for antitubercular chemotherapy. It is encoded by genes dprE1 (Rv3790) and dprE2 (Rv3791). Three-dimensional (3D) structure prediction of selected target (461 amino acid residues) was intent by homology modeling using multitemplate approach based on crystal structure of 2EXR...
May 5, 2016: Interdisciplinary Sciences, Computational Life Sciences
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