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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...
October 4, 2016: 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...
September 22, 2016: 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
T S Chitre, K D Asgaonkar, P B Miniyar, A B Dharme, M A Arkile, A Yeware, D Sarkar, V M Khedkar, P C Jha
The persistence of Mycobacterium tuberculosis (MTB) in dormant stage assists the pathogen to develop resistance against current antimycobactrial drugs. To address this issue, we report herein the synthesis of N-(4-oxo-2 substituted thiazolidin-3 yl) pyrazine-2-carbohydrazide derivatives designed by following the molecular hybridization approach using pyrazine and thiazolidenone scaffolds. The compounds were evaluated against MTB H37Ra and Mycobacterium bovis BCG in dormancy model. Most of the compounds had IC50 values in 0...
May 1, 2016: Bioorganic & Medicinal Chemistry Letters
Rohit Tiwari, Patricia A Miller, Laurent R Chiarelli, Giorgia Mori, Michal Šarkan, Ivana Centárová, Sanghyun Cho, Katarína Mikušová, Scott G Franzblau, Allen G Oliver, Marvin J Miller
Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity...
March 10, 2016: ACS Medicinal Chemistry Letters
Sudhir Landge, Vasanthi Ramachandran, Anupriya Kumar, João Neres, Kannan Murugan, Claire Sadler, Mick D Fellows, Vaishali Humnabadkar, Prakash Vachaspati, Anandkumar Raichurkar, Sreevalli Sharma, Sudha Ravishankar, Supreeth Guptha, Vasan K Sambandamurthy, Tanjore S Balganesh, Bheemarao G Ugarkar, V Balasubramanian, Balachandra S Bandodkar, Manoranjan Panda
Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non-enzymatic, in mycobacteria prior to binding to the target of interest. From a whole-cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis (Mtb)...
February 4, 2016: ChemMedChem
Sudhir Landge, Amrita B Mullick, Kavitha Nagalapur, João Neres, Venkita Subbulakshmi, Kannan Murugan, Anirban Ghosh, Claire Sadler, Mick D Fellows, Vaishali Humnabadkar, Jyothi Mahadevaswamy, Prakash Vachaspati, Sreevalli Sharma, Parvinder Kaur, Meenakshi Mallya, Suresh Rudrapatna, Disha Awasthy, Vasan K Sambandamurthy, Florence Pojer, Stewart T Cole, Tanjore S Balganesh, Bheemarao G Ugarkar, V Balasubramanian, Balachandra S Bandodkar, Manoranjan Panda, Vasanthi Ramachandran
We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs)...
December 15, 2015: Bioorganic & Medicinal Chemistry
Mubarak H Shaikh, Dnyaneshwar D Subhedar, Manisha Arkile, Vijay M Khedkar, Nandadeep Jadhav, Dhiman Sarkar, Bapurao B Shingate
In search of new active molecules against Mycobacterium tuberculosis (MTB) H37Ra and M. bovis BCG, a small focused library of benzothiazinone based 1,2,3-triazoles has been efficiently prepared via click chemistry approach. Several derivatives were found to be promising inhibitors of MTB and M. bovis BCG characterized by lower MIC values (27.34-29.37μg/mL). Among all the synthesized compounds, 6c and 6e is the most active compound against MTB and M. bovis BCG. The compounds were further tested for anti-proliferative activity against HeLa, A549 and A431 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated...
January 15, 2016: Bioorganic & Medicinal Chemistry Letters
Norma Alejandra González-Martínez, Hector Gerardo Lozano-Garza, Jorge Castro-Garza, Alexandra De Osio-Cortez, Javier Vargas-Villarreal, Norma Cavazos-Rocha, Jorge Ocampo-Candiani, Vadim Makarov, Stewart T Cole, Lucio Vera-Cabrera
BACKGROUND: Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ) are a new class of candidate drugs that inhibit decaprenyl-phosphoribose-epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the in vitro activity of the next generation BTZ, PBTZ169, was tested against thirty Nocardia brasiliensis isolates...
2015: PLoS Neglected Tropical Diseases
Gaëlle S Kolly, Raju Mukherjee, Emöke Kilacsková, Luciano A Abriata, Mahé Raccaud, Jaroslav Blaško, Claudia Sala, Matteo Dal Peraro, Katarína Mikušová, Stewart T Cole
UNLABELLED: Mycobacterium tuberculosis possesses a thick and highly hydrophobic cell wall principally composed of a mycolyl-arabinogalactan-peptidoglycan complex, which is critical for survival and virulence. DprE1 is a well-characterized component of decaprenyl-phospho-ribose epimerase, which produces decaprenyl-phospho-arabinose (DPA) for the biosynthesis of mycobacterial arabinans. Upstream of dprE1 lies rv3789, which encodes a short transmembrane protein of the GtrA family, whose members are often involved in the synthesis of cell surface polysaccharides...
December 2015: Journal of Bacteriology
Vandana S Pore, Jaisingh M Divse, Chaitanya R Charolkar, Laxman U Nawale, Vijay M Khedkar, Dhiman Sarkar
We have synthesized a series of novel 11α-triazoyl bile acid derivatives. In addition, we also have synthesized N-alkyl and N-acyl derivatives of C-11 amino bile acid esters. All the compounds were evaluated for the inhibitory activity against Mycobacterium tuberculosis H37Ra (MTB) at 30 μg/mL level. Four lead compounds (2b, 3, 7 and 8) were further confirmed from their dose dependent effect against MTB. These compounds were found to be active against Dormant and active stage MTB under both in vitro as well as within THP1 host macrophages...
October 1, 2015: Bioorganic & Medicinal Chemistry Letters
Vadim Makarov, João Neres, Ruben C Hartkoorn, Olga B Ryabova, Elena Kazakova, Michal Šarkan, Stanislav Huszár, Jérémie Piton, Gaëlle S Kolly, Anthony Vocat, Trent M Conroy, Katarína Mikušová, Stewart T Cole
8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity...
August 2015: Antimicrobial Agents and Chemotherapy
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
April 9, 2015: ACS Medicinal Chemistry Letters
Miroslav Brecik, Ivana Centárová, Raju Mukherjee, Gaëlle S Kolly, Stanislav Huszár, Adela Bobovská, Emöke Kilacsková, Veronika Mokošová, Zuzana Svetlíková, Michal Šarkan, João Neres, Jana Korduláková, Stewart T Cole, Katarína Mikušová
The flavo-enzyme DprE1 catalyzes a key epimerization step in the decaprenyl-phosphoryl d-arabinose (DPA) pathway, which is essential for mycobacterial cell wall biogenesis and targeted by several new tuberculosis drug candidates. Here, using differential radiolabeling with DPA precursors and high-resolution fluorescence microscopy, we disclose the unexpected extracytoplasmic localization of DprE1 and periplasmic synthesis of DPA. Collectively, this explains the vulnerability of DprE1 and the remarkable potency of the best inhibitors...
July 17, 2015: ACS Chemical Biology
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