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572 results on '"Boshoff, Helena I."'

1. Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Author

Green, Simon R., Davis, Susan H., Damerow, Sebastian, Engelhart, Curtis A., Mathieson, Michael, Baragaña, Beatriz, Robinson, David A., Tamjar, Jevgenia, Dawson, Alice, Tamaki, Fabio K., Buchanan, Kirsteen I., Post, John, Dowers, Karen, Shepherd, Sharon M., Jansen, Chimed, Zuccotto, Fabio, Gilbert, Ian H., Epemolu, Ola, Riley, Jennifer, Stojanovski, Laste, Osuna-Cabello, Maria, Pérez-Herrán, Esther, Rebollo, María José, Guijarro López, Laura, Casado Castro, Patricia, Camino, Isabel, Kim, Heather C., Bean, James M., Nahiyaan, Navid, Rhee, Kyu Y., Wang, Qinglan, Tan, Vee Y., Boshoff, Helena I. M., Converse, Paul J., Li, Si-Yang, Chang, Yong S., Fotouhi, Nader, Upton, Anna M., Nuermberger, Eric L., Schnappinger, Dirk, Read, Kevin D., Encinas, Lourdes, Bates, Robert H., Wyatt, Paul G., and Cleghorn, Laura A. T.

Published
2022
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4. The Tuberculosis Drug Accelerator at year 10: what have we learned?

Author

Aldridge, Bree B., Barros-Aguirre, David, Barry, Clifton E., III, Bates, Robert H., Berthel, Steven J., Boshoff, Helena I., and Chibale, Kelly

Subjects
Drug discovery -- Forecasts and trends, Tuberculosis -- Diagnosis -- Drug therapy, Consortia -- Achievements and awards, Consortium, Market trend/market analysis, Biological sciences, Health
Abstract

The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in tuberculosis drug discovery by breaking down barriers among competing labs and institutions, has reached a 10-year landmark. We review the consortium's achievements, advantages and limitations and advocate for the application of similar models to other diseases., Author(s): Bree B. Aldridge [sup.1] , David Barros-Aguirre [sup.2] , Clifton E. Barry III [sup.3] , Robert H. Bates [sup.2] , Steven J. Berthel [sup.4] , Helena I. Boshoff [sup.3] [...]

Published
2021
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7. Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

Author

Costa, Diego L, Namasivayam, Sivaranjani, Amaral, Eduardo P, Arora, Kriti, Chao, Alex, Mittereder, Lara R, Maiga, Mamoudou, Boshoff, Helena I, Barry, Clifton E, Goulding, Celia W, Andrade, Bruno B, and Sher, Alan

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Lung, Orphan Drug, Rare Diseases, Antimicrobial Resistance, Biodefense, Infectious Diseases, Emerging Infectious Diseases, Tuberculosis, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, 6.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, Animals, Bacterial Load, Disease Models, Animal, Enzyme Inhibitors, Heme Oxygenase-1, Immunologic Factors, Metalloporphyrins, Mice, Mycobacterium tuberculosis, Protoporphyrins, T-Lymphocytes, Treatment Outcome, Microbiology, Biochemistry and cell biology, Medical microbiology
Abstract

Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function.ImportanceThere is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB.

Published
2016

9. Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

Author

Mendes, Vitor, Green, Simon R., Evans, Joanna C., Hess, Jeannine, Blaszczyk, Michal, Spry, Christina, Bryant, Owain, Cory-Wright, James, Chan, Daniel S-H., Torres, Pedro H. M., Wang, Zhe, Nahiyaan, Navid, O’Neill, Sandra, Damerow, Sebastian, Post, John, Bayliss, Tracy, Lynch, Sasha L., Coyne, Anthony G., Ray, Peter C., Abell, Chris, Rhee, Kyu Y., Boshoff, Helena I. M., Barry, III, Clifton E., Mizrahi, Valerie, Wyatt, Paul G., and Blundell, Tom L.

Published
2021
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13. Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

Author

Green, Simon R., primary, Wilson, Caroline, additional, Eadsforth, Thomas C., additional, Punekar, Avinash S., additional, Tamaki, Fabio K., additional, Wood, Gavin, additional, Caldwell, Nicola, additional, Forte, Barbara, additional, Norcross, Neil R., additional, Kiczun, Michael, additional, Post, John M., additional, Lopez-Román, Eva Maria, additional, Engelhart, Curtis A., additional, Lukac, Iva, additional, Zuccotto, Fabio, additional, Epemolu, Ola, additional, Boshoff, Helena I. M., additional, Schnappinger, Dirk, additional, Walpole, Chris, additional, Gilbert, Ian H., additional, Read, Kevin D., additional, Wyatt, Paul G., additional, and Baragaña, Beatriz, additional

Published
2023
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18. Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis

Author

Katariya, Mona M., primary, Snee, Matthew, additional, Tunnicliffe, Richard B., additional, Kavanagh, Madeline E., additional, Boshoff, Helena I. M., additional, Amadi, Cecilia N., additional, Levy, Colin W., additional, Munro, Andrew W., additional, Abell, Chris, additional, Leys, David, additional, Coyne, Anthony G., additional, and McLean, Kirsty J, additional

Published
2023
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23. Inhibition of DXR in the MEP pathway with lipophilic N-alkoxyaryl FR900098 analogsElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3md00642e

Author

Bague, Darean, Wang, Ruiqin, Hodge, Dana, Mikati, Marwa O., Roma, Jose S., Boshoff, Helena I., Dailey, Allyson L., Girma, Misgina, Couch, Robin D., Odom John, Audrey R., and Dowd, Cynthia S.

Abstract

In Mycobacterium tuberculosis(Mtb) and Plasmodium falciparum(Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. This pathway and its products are vital to bacterial/parasitic metabolism and survival, and represent an attractive set of drug targets due to their essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR). Natural products fosmidomycin and FR900098 inhibit DXR, but are too polar to reach the desired target inside some cells, such as Mtb. Synthesized FR900098 analogs with lipophilic substitution in the position α to the phosphorous atom showed promise, resulting in increased activity against Mtband Pf. Here, an α substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O-linked alkylaryl substituents on the hydroxamate moiety is utilized in the synthesis of a novel series of FR900098 analogs. The purpose of the O-linked alkylaryl substituents is to further enhance DXR inhibition by extending the structure into the adjacent NADPH binding pocket, blocking the binding of both DXP and NADPH. Of the initial O-linked alkylaryl substituted analogs, compound 6eshowed most potent activity against Pfparasites at 3.60 μM. Additional compounds varying the phenyl ring of 6ewere synthesized. The most potent phosphonic acids, 6land 6n, display nM activity against PfDXR and low μM activity against Pfparasites. Prodrugs of these compounds were less effective against Pfparasites but showed modest activity against Mtbcells. Data from this series of compounds suggests that this combination of substituents can be advantageous in designing a new generation of antimicrobials.

Published
2024
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24. Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development

Author

Beites, Tiago, O’Brien, Kathryn, Tiwari, Divya, Engelhart, Curtis A., Walters, Shaun, Andrews, Jenna, Yang, Hee-Jeong, Sutphen, Michelle L., Weiner, Danielle M., Dayao, Emmanuel K., Zimmerman, Matthew, Prideaux, Brendan, Desai, Prashant V., Masquelin, Thierry, Via, Laura E., Dartois, Véronique, Boshoff, Helena I., Barry, III, Clifton E., Ehrt, Sabine, and Schnappinger, Dirk

Published
2019
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25. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

Author

Koller, Timm O., primary, Scheid, Ullrich, additional, Kösel, Teresa, additional, Herrmann, Jennifer, additional, Krug, Daniel, additional, Boshoff, Helena I. M., additional, Beckert, Bertrand, additional, Evans, Joanna C., additional, Schlemmer, Jan, additional, Sloan, Becky, additional, Weiner, Danielle M., additional, Via, Laura E., additional, Moosa, Atica, additional, Ioerger, Thomas R., additional, Graf, Michael, additional, Zinshteyn, Boris, additional, Abdelshahid, Maha, additional, Nguyen, Fabian, additional, Arenz, Stefan, additional, Gille, Franziska, additional, Siebke, Maik, additional, Seedorf, Tim, additional, Plettenburg, Oliver, additional, Green, Rachel, additional, Warnke, Anna-Luisa, additional, Ullrich, Joachim, additional, Warrass, Ralf, additional, Barry, Clifton E., additional, Warner, Digby F., additional, Mizrahi, Valerie, additional, Kirschning, Andreas, additional, Wilson, Daniel N., additional, and Müller, Rolf, additional

Published
2023
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27. The Medicinal Chemistry of Tuberculosis Chemotherapy

Author

Marriner, Gwendolyn A., Nayyar, Amit, Uh, Eugene, Wong, Sharon Y., Mukherjee, Tathagata, Via, Laura E., Carroll, Matthew, Edwards, Rachel L., Gruber, Todd D., Choi, Inhee, Lee, Jinwoo, Arora, Kriti, England, Kathleen D., Boshoff, Helena I. M., Barry, Clifton E., III, and Elliott, Richard, editor

Published
2011
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28. The myxobacterial antibiotic myxovalargin: Biosynthesis, structural revision, total synthesis and molecular characterization of ribosomal inhibition

Author

Koller, Timm O., primary, Scheid, Ullrich, additional, Kösel, Teresa, additional, Herrmann, Jennifer, additional, Krug, Daniel, additional, Boshoff, Helena I., additional, Beckert, Bertrand, additional, Evans, Joanna C., additional, Schlemmer, Jan, additional, Sloan, Becky, additional, Weiner, Danielle M., additional, Via, Laura E., additional, Moosa, Atica, additional, Ioerger, Thomas R., additional, Gille, Franziska, additional, Siebke, Maik, additional, Seedorf, Tim, additional, Plettenburg, Oliver, additional, Warnke, Anna-Luisa, additional, Ullrich, Joachim, additional, Warrass, Ralf, additional, Barry, Clifton E., additional, Warner, Digby F., additional, Mizrahi, Valerie, additional, Kirschning, Andreas, additional, Wilson, Daniel N., additional, and Müller, Rolf, additional

Published
2022
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29. GSK2556286 Is a Novel Antitubercular Drug Candidate Effective In Vivo with the Potential To Shorten Tuberculosis Treatment

Author

Nuermberger, Eric L., primary, Martínez-Martínez, Maria Santos, additional, Sanz, Olalla, additional, Urones, Beatriz, additional, Esquivias, Jorge, additional, Soni, Heena, additional, Tasneen, Rokeya, additional, Tyagi, Sandeep, additional, Li, Si-Yang, additional, Converse, Paul J., additional, Boshoff, Helena I., additional, Robertson, Gregory T., additional, Besra, Gurdyal S., additional, Abrahams, Katherine A., additional, Upton, Anna M., additional, Mdluli, Khisimuzi, additional, Boyle, Gary W., additional, Turner, Sam, additional, Fotouhi, Nader, additional, Cammack, Nicholas C., additional, Siles, Juan Miguel, additional, Alonso, Marta, additional, Escribano, Jaime, additional, Lelievre, Joel, additional, Rullas-Trincado, Joaquin, additional, Pérez-Herrán, Esther, additional, Bates, Robert H., additional, Maher-Edwards, Gareth, additional, Barros, David, additional, Ballell, Lluís, additional, and Jiménez, Elena, additional

Published
2022
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37. Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions

Author

Gold, Ben, primary, Zhang, Jun, additional, Quezada, Landys Lopez, additional, Roberts, Julia, additional, Ling, Yan, additional, Wood, Madeleine, additional, Shinwari, Wasima, additional, Goullieux, Laurent, additional, Roubert, Christine, additional, Fraisse, Laurent, additional, Bacqué, Eric, additional, Lagrange, Sophie, additional, Filoche-Rommé, Bruno, additional, Vieth, Michal, additional, Hipskind, Philip A., additional, Jungheim, Louis N., additional, Aubé, Jeffrey, additional, Scarry, Sarah M., additional, McDonald, Stacey L., additional, Li, Kelin, additional, Perkowski, Andrew, additional, Nguyen, Quyen, additional, Dartois, Véronique, additional, Zimmerman, Matthew, additional, Olsen, David B., additional, Young, Katherine, additional, Bonnett, Shilah, additional, Joerss, Douglas, additional, Parish, Tanya, additional, Boshoff, Helena I., additional, Arora, Kriti, additional, Barry, Clifton E., additional, Guijarro, Laura, additional, Anca, Sara, additional, Rullas, Joaquín, additional, Rodríguez-Salguero, Beatriz, additional, Martínez-Martínez, Maria S., additional, Porras-De Francisco, Esther, additional, Cacho, Monica, additional, Barros-Aguirre, David, additional, Smith, Paul, additional, Berthel, Steven J., additional, Nathan, Carl, additional, and Bates, Robert H., additional

Published
2022
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38. DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis

Author

Chengalroyen, Melissa D., primary, Mason, Mandy K., additional, Borsellini, Alessandro, additional, Tassoni, Raffaella, additional, Abrahams, Garth L., additional, Lynch, Sasha, additional, Ahn, Yong-Mo, additional, Ambler, Jon, additional, Young, Katherine, additional, Crowley, Brendan M., additional, Olsen, David B., additional, Warner, Digby F., additional, Barry III, Clifton E., additional, Boshoff, Helena I. M., additional, Lamers, Meindert H., additional, and Mizrahi, Valerie, additional

Published
2022
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40. Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

Author

Chacko, Shibin, primary, Boshoff, Helena I. M., additional, Singh, Vinayak, additional, Ferraris, Davide M., additional, Gollapalli, Deviprasad R., additional, Zhang, Minjia, additional, Lawson, Ann P., additional, Pepi, Michael J., additional, Joachimiak, Andrzej, additional, Rizzi, Menico, additional, Mizrahi, Valerie, additional, Cuny, Gregory D., additional, and Hedstrom, Lizbeth, additional

Published
2021
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41. Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux

Author

Lee, Richard E., Hurdle, Julian G., Liu, Jiuyu, Bruhn, David F., Matt, Tanja, Scherman, Michael S., Vaddady, Pavan K., Zheng, Zhong, Qi, Jianjun, Akbergenov, Rashid, Das, Sourav, Madhura, Dora B., Rathi, Chetan, Trivedi, Ashit, Villellas, Cristina, Lee, Robin B., Waidyarachchi, Samanthi L., Sun, Dianqing, McNeil, Michael R., Ainsa, Jose A., Boshoff, Helena I., Gonzalez-Juarrero, Mercedes, Meibohm, Bernd, Bottger, Erik C., and Lenaerts, Anne J.

Subjects
Antitubercular agents -- Product development, Drug discovery -- Research, Biological sciences, Health
Abstract

Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic [...]

Published
2014

43. 1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

Author

Khonde, Lutete Peguy, Müller, Rudolf, Boyle, Grant A., Reddy, Virsinha, Nchinda, Aloysius T., Eyermann, Charles J., Fienberg, Stephen, Singh, Vinayak, Myrick, Alissa, Abay, Efrem, Njoroge, Mathew, Lawrence, Nina, Su, Qin, Myers, Timothy G., Boshoff, Helena I. M., Barry, Clifton E., Sirgel, Frederick A., van Helden, Paul D., Massoudi, Lisa M., Robertson, Gregory T., Lenaerts, Anne J., Basarab, Gregory S., Ghorpade, Sandeep R., and Chibale, Kelly

Abstract

This is the accepted manuscript version of the work published in its final form as Khonde, Lutete Peguy;Müller, Rudolf;Boyle, Grant A.;Reddy, Virsinha;Nchinda, Aloysius T.;Eyermann, Charles J.;Fienberg, Stephen;Singh, Vinayak;Myrick, Alissa;Abay, Efrem;Njoroge, Mathew;Lawrence, Nina;Su, Qin;Myers, Timothy G.;Boshoff, Helena I. M.;Barry, Clifton E.;Sirgel, Frederick A.;van Helden, Paul D.;Massoudi, Lisa M.;Robertson, Gregory T.;Lenaerts, Anne J.;Basarab, Gregory S.;Ghorpade, Sandeep R.;Chibale, Kelly. Journal of Medicinal Chemistry Volume: 64 issue: 17, page(s): 12790–12807.https://doi.org/10.1021/acs.jmedchem.1c00837 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.

Published
2021
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45. 1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

Author

Khonde, Lutete Peguy, primary, Müller, Rudolf, additional, Boyle, Grant A., additional, Reddy, Virsinha, additional, Nchinda, Aloysius T., additional, Eyermann, Charles J., additional, Fienberg, Stephen, additional, Singh, Vinayak, additional, Myrick, Alissa, additional, Abay, Efrem, additional, Njoroge, Mathew, additional, Lawrence, Nina, additional, Su, Qin, additional, Myers, Timothy G., additional, Boshoff, Helena I. M., additional, Barry, Clifton E., additional, Sirgel, Frederick A., additional, van Helden, Paul D., additional, Massoudi, Lisa M., additional, Robertson, Gregory T., additional, Lenaerts, Anne J., additional, Basarab, Gregory S., additional, Ghorpade, Sandeep R., additional, and Chibale, Kelly, additional

Published
2021
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47. Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase

Author

Song, Taeksun, Park, Yumi, Shamputa, Isdore Chola, Seo, Sunghwa, Lee, Sun Young, Jeon, Han-Seung, Choi, Hongjo, Lee, Myungsun, Glynne, Richard J., Barnes, Whitney S., Walker, John R., Batalov, Serge, Yusim, Karina, Feng, Shihai, Tung, Chang-Shung, Theiler, James, Via, Laura E., Boshoff, Helena I. M., Murakami, Katsuhiko S., Korber, Bette, Barry, Clifton E., 3rd, and Cho, Sang-Nae

Published
2014
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48. Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4′-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity

Author

Evans, Joanna C., primary, Murugesan, Dinakaran, additional, Post, John M., additional, Mendes, Vitor, additional, Wang, Zhe, additional, Nahiyaan, Navid, additional, Lynch, Sasha L., additional, Thompson, Stephen, additional, Green, Simon R., additional, Ray, Peter C., additional, Hess, Jeannine, additional, Spry, Christina, additional, Coyne, Anthony G., additional, Abell, Chris, additional, Boshoff, Helena I. M., additional, Wyatt, Paul G., additional, Rhee, Kyu Y., additional, Blundell, Tom L., additional, Barry, Clifton E., additional, and Mizrahi, Valerie, additional

Published
2021
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50. 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

Author

Murugesan, Dinakaran, Ray, Peter C., Bayliss, Tracy, Prosser, Gareth A., Harrison, Justin R., Green, Kirsteen, Soares de Melo, Candice, Feng, Tzu-Shean, Street, Leslie J., Chibale, Kelly, Warner, Digby F., Mizrahi, Valerie, Epemolu, Ola, Scullion, Paul, Ellis, Lucy, Riley, Jennifer, Shishikura, Yoko, Ferguson, Liam, Osuna-Cabello, Maria, Read, Kevin D., Green, Simon R., Lamprecht, Dirk A., Finin, Peter M., Steyn, Adrie J. C., Ioerger, Thomas R., Sacchettini, Jim, Rhee, Kyu Y., Arora, Kriti, Barry, Clifton E., Wyatt, Paul G., and Boshoff, Helena I. M.

Subjects
structure−activity relationship, Structure-Activity Relationship, mercapto-quinazolinones, Molecular Structure, type II NADH dehydrogenase, NADH Dehydrogenase, Mycobacterium tuberculosis, Article, small molecule NDH-2 inhibitors, respiration, Quinazolinones
Abstract

Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

Published
2018

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