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10. The challenge of new drug discovery for tuberculosis

Author

Koul, Anil, Arnoult, Eric, Lounis, Nacer, Guillemont, Jerome, and Andries, Koen

Subjects
Antitubercular agents -- Discovery and exploration -- Dosage and administration -- Research, Drug targeting -- Research -- Discovery and exploration, Tuberculosis -- Drug therapy -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients., In 1882, Robert Koch identified Mycobacterium tuberculosis as the causative agent of TB, but since his discovery the global TB epidemic seems unabated; this year it is anticipated that there [...]

Published
2011
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13. The diarylquinoline TMC207 for multidrug-resistant tuberculosis

Author

Diacon, Andreas H., Pym, Alexander, Grobusch, Martin, Patientia, Ramonde, Rustomjee, Roxana, Page-Shipp, Liesl, Pistorius, Christoffel, Krause, Rene, Bogoshi, Mampedi, Churchyard, Gavin, Venter, Amour, Allen, Jenny, Palomino, Juan Carlos, De Marez, Tine, van Heeswijk, Rolf P.G., Lounis, Nacer, Meyisch, Paul, Verbeeck, Johnan, Parys, Wim, de Beule, Karel, Andries, Koen, and McNeeley, David F.

Subjects
Tuberculosis -- Drug therapy, Tuberculosis -- Care and treatment, Antitubercular agents -- Usage, Antitubercular agents -- Health aspects
Abstract

A randomized, controlled trial is conducted to test the efficacy and safety of using diarylquinoline TMC207, which inhibits mycobacterial ATP synthase as a mechanism of antituberculosis action, in the treatment of multidrug-resistant tuberculosis. Results reveal that TMC207 is safe and effective, thus validating ATP synthase as a target for antituberculosis therapy.

Published
2009

14. Potential use of antiviral agents in polio eradication

Author

De Palma, Armando M., Purstinger, Gerhard, Wimmer, Eva, Patick, Amy K., Andries, Koen, Rombaut, Bart, De Clercq, Erik, and Neyts, Johan

Subjects
Company distribution practices, Antiviral agents -- Dosage and administration, Poliomyelitis -- Risk factors, Poliomyelitis -- Distribution, Poliomyelitis -- Drug therapy, Poliomyelitis -- Control, Poliomyelitis -- Research
Abstract

In 1988, the World Health Assembly launched the Global Polio Eradication Initiative, which aimed to use large-scale vaccination with the oral vaccine to eradicate polio worldwide by the year 2000. [...]

Published
2008

16. Correlations between Factors Determining the Pharmacokinetics and Antiviral Activity of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors of the Diaryltriazine and Diarylpyrimidine Classes of Compounds

Author

Lewi, Paul, Arnold, Eddy, Andries, Koen, Bohets, Hilde, Borghys, Herman, Clark, Arthur, Daeyaert, Frits, Das, Kalyan, de Béthune, Marie-Pierre, de Jonge, Marc, Heeres, Jan, Koymans, Luc, Leempoels, Jos, Peeters, Jef, Timmerman, Philip, Van den Broeck, Walter, Vanhoutte, Frédéric, van’t Klooster, Gerben, Vinkers, Maarten, Volovik, Yulia, and Janssen, Paul A. J.

Published
2004
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17. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis

Author

Andries, Koen, Verhasselt, Peter, Guillemont, Jerome, Gohlmann, Hinrich W.H., Neefs, Jean-Marc, Winkler, Hans, Van Gestel, Jef, Timmerman, Philip, Zhu, Min, Lee, Ennis, Williams, Peter, de Chaffoy, Didier, Huitric, Emma, Hoffner, Sven, Cambau, Emmanuelle, Truffot-Pernot, Chantal, Lounis, Nacer, and Jarlier, Vincent

Subjects
Adenosine triphosphatase -- Research -- Usage, Respiratory agents -- Research -- Usage, Tuberculosis -- Research -- Care and treatment, Mice -- Research -- Usage, Science and technology
Abstract

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 µg/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single close of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase., After AIDS, tuberculosis (TB) is the leading cause of infectious disease mortality in the world, with 2 million to 3 million deaths per year (1). The TB and HIV epidemics [...]

Published
2005

26. 6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

Author

Tong, Amy S. T., Choi, Peter J., Blaser, Adrian, Sutherland, Hamish S., Tsang, Sophia K. Y., Guillemont, Jerome, Motte, Magali, Cooper, Christopher B., Andries, Koen, Van den Broeck, Walter, Franzblau, Scott G., Upton, Anna M., Denny, William A., Palmer, Brian D., and Conole, Daniel

Subjects
Letter, tuberculosis, Bedaquiline, lipophilicity, ATP synthase, hERG, diarylquinoline
Abstract

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

Published
2017

28. Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

Author

Choi, Peter J., Sutherland, Hamish S., Tong, Amy S.T., Blaser, Adrian, Franzblau, Scott G., Cooper, Christopher B., Lotlikar, Manisha U., Upton, Anna M., Guillemont, Jerome, Motte, Magali, Queguiner, Laurence, Andries, Koen, Van den Broeck, Walter, Denny, William A., and Palmer, Brian D.

Subjects
ERG1 Potassium Channel, Bedaquiline, Antitubercular Agents, Administration, Oral, Drug development, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Article, Rats, Inhibitory Concentration 50, Structure-Activity Relationship, Bedaquiline analogues, Heterocyclic Compounds, Microsomes, Liver, Tuberculosis, Animals, Humans, Diarylquinolines, ComputingMethodologies_COMPUTERGRAPHICS, Half-Life
Abstract

Graphical abstract, Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.

Published
2017

34. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase

Author

Pauwells, Rudi, Andries, Koen, Debyser, Zeger, Van Daele, Paul, Schols, Dominique, Stoffels, Paul, De Vreese, Karen, Woestenborghs, Robert, Vandamme, Anne-Mieke, Janssen, Cornelus G.M., Anne, Jef, Cauwenbergh, Geert, Desmyter, Jan, Heykants, Jozef, Janssen, Marcel A.C., De Clerq, Erik, and Janssen, Paul A.J.

Subjects
HIV (Viruses) -- Inactivation, AIDS (Disease) -- Care and treatment, Reverse transcriptase -- Research, Antiviral agents -- Identification and classification, Science and technology
Abstract

A high-flux screen of 2,000 compounds obtained from a chemical library resulted in the identification of alpha-anilinophenylacetamide(alpha-APA) derivatives as potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. These inhibitors apparently target the viral reverse transcriptase and are effective at nanomolar concentrations. One of thederivatives, R 89439, has good oral availability, favorable pharmacokinetics and can be easily synthesized.

Published
1993

35. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives

Author

Pauwels, Rudi, Andries, Koen, Desmyter, Jan, Schols, Dominique, Kukla, Michael J., Breslin, Henry J., Raeymaeckers, Alfons, Van Gelder, Jozef, Woestensborghs, Robert, Heykants, Jozef, Schellekens, Karel, Janssen, Marcel A.C., De Clercq, Erik, and Janssen, Paul A.J.

Subjects
AIDS (Disease) -- Drug therapy, HIV (Viruses) -- Reproduction, Antiviral agents -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The search for effective treatments for AIDS has focused on the biology of the human immunodeficiency viruses (HIV). A new set of organic chemical compounds, called TIBO derivatives for brevity, seems to be effective in suppressing the replication of HIV-1, the main etiological agent of AIDS, but not HIV-2 or other viruses tested. These chemical agents are unusual in that, unlike many antiviral agents, the suppression is highly specific for a particular virus. In direct contrast to AZT, a current AIDS therapeutic agent being given widespread trials, the dosage of TIBO compounds necessary to suppress the virus in tissue culture is 10,000 to 100,000 times less than the toxic dose. The effective dose of AZT in tissue culture is only 100 to 10,000 times less than the toxic dose. Clearly, the less toxic the effective dose, the easier it is for clinicians to maintain effective blood concentrations of the therapeutic agent in their patients. Although TIBO derivatives have not yet been tried in AIDS patients, preliminary studies in healthy male volunteers show that no adverse affects were seen at doses 1,000 times greater than the IC-50 (that dose necessary to suppress half the HIV-1 in tissue culture cells). A 200 mg dose resulted in blood levels exceeding the IC-50 for over 24 hours. No significant laboratory changes were observed in these volunteers and the drugs seem to be well tolerated, setting the stage for preliminary evaluations in AIDS patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1990

41. In vitro activity of bedaquiline against rapidly growing nontuberculous mycobacteria.

Author

UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, Aguilar-Ayala, Diana A, Cnockaert, Margo, André, Emmanuel, Andries, Koen, Gonzalez-Y-Merchand, Jorge A, Vandamme, Peter, Palomino, Juan Carlos, Martin, Anandi, UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, Aguilar-Ayala, Diana A, Cnockaert, Margo, André, Emmanuel, Andries, Koen, Gonzalez-Y-Merchand, Jorge A, Vandamme, Peter, Palomino, Juan Carlos, and Martin, Anandi

Abstract

Bedaquiline (BDQ) has been proven to be effective in the treatment of multidrug-resistant tuberculosis. We hypothesized that BDQ could be a potential agent to treat nontuberculous mycobacterial (NTM) infection. The objective of this study was to evaluate the in vitro activity of BDQ against rapidly growing mycobacteria by assessing the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against 18 NTM strains. For MIC determination we performed the resazurin microtitre assay broth dilution, and for the MBC the c.f.u. was determined. BDQ exhibited a strong inhibitory effect against most NTM tested; however, for some NTM strains the MBC was significantly higher than the MIC. A new finding is that Mycobacterium flavescens has a mutation in the gene atpE associated with natural resistance to BDQ. These preliminary promising results demonstrate that BDQ could be potentially useful for the treatment of NTM.

Published
2017

47. Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice

Author

Irwin, Scott M., primary, Prideaux, Brendan, additional, Lyon, Edward R., additional, Zimmerman, Matthew D., additional, Brooks, Elizabeth J., additional, Schrupp, Christopher A., additional, Chen, Chao, additional, Reichlen, Matthew J., additional, Asay, Bryce C., additional, Voskuil, Martin I., additional, Nuermberger, Eric L., additional, Andries, Koen, additional, Lyons, Michael A., additional, Dartois, Véronique, additional, and Lenaerts, Anne J., additional

Published
2016
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49. Synthesis, characterization and biological activity of fluorescently labeled bedaquiline analogues

Author

Rombouts, Jeroen A., primary, Veenboer, Richard M. P., additional, Villellas, Cristina, additional, Lu, Ping, additional, Ehlers, Andreas W., additional, Andries, Koen, additional, Koul, Anil, additional, Lill, Holger, additional, Ruijter, Eelco, additional, Orru, Romano V. A., additional, Lammertsma, Koop, additional, Bald, Dirk, additional, and Slootweg, J. Chris, additional

Published
2016
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50. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Author

Pym, Alexander S., primary, Diacon, Andreas H., additional, Tang, Shen-Jie, additional, Conradie, Francesca, additional, Danilovits, Manfred, additional, Chuchottaworn, Charoen, additional, Vasilyeva, Irina, additional, Andries, Koen, additional, Bakare, Nyasha, additional, De Marez, Tine, additional, Haxaire-Theeuwes, Myriam, additional, Lounis, Nacer, additional, Meyvisch, Paul, additional, Van Baelen, Ben, additional, van Heeswijk, Rolf P.G., additional, and Dannemann, Brian, additional

Published
2015
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