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9. 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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11. 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

12. 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

16. In vitro activity of bedaquiline against slow-growing nontuberculous mycobacteria.

Author

UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, Martin, Anandi, Torres Godino, Isabel, Aguilar-Ayala, Diana Angelica, Mathys, Vanessa, Lounis, Nacer, Rodriguez-Villalobos, Hector, UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, Martin, Anandi, Torres Godino, Isabel, Aguilar-Ayala, Diana Angelica, Mathys, Vanessa, Lounis, Nacer, and Rodriguez-Villalobos, Hector

Abstract

Bedaquiline (BDQ) is a recently approved antibiotic for the treatment of multidrug-resistant tuberculosis, but its potential against slow-growing mycobacteria (SGM) is still unknown. The objective of this study was to determine the in vitro activity of BDQ on SGM by assessing their MIC and minimal bactericidal concentration (MBC). The MIC of BDQ against 17 clinical isolates including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium kansasii and Mycobacterium simiae species was determined by the resazurin microtitre assay and the MBC by the c.f.u. determination on 7H10 agar plates. BDQ has a bacteriostatic activity on all SGM tested with a MIC range from 0.03 to 0.007 µg ml and surprisingly a good bactericidal activity on the majority of the isolates tested with an MBC of 1-2 µg ml . Based on these preliminary results BDQ seems to be very promising for treatment of diseases caused by SGM.

Published
2019

24. A Multilaboratory, Multicountry Study To Determine MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing of Selected First-Line Antituberculosis Drugs, Second-Line Injectables, Fluoroquinolones, Clofazimine, and Linezolid

Author

Kaniga, Koné, primary, Cirillo, Daniela M., additional, Hoffner, Sven, additional, Ismail, Nazir A., additional, Kaur, Devinder, additional, Lounis, Nacer, additional, Metchock, Beverly, additional, Pfyffer, Gaby E., additional, and Venter, Amour, additional

Published
2016
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27. Effect of Oral JNJ-53718678 (JNJ-678) on Disease Severity in Healthy Adult Volunteers Experimentally Inoculated With Live Respiratory Syncytial Virus (RSV): A Placebo-Controlled Challenge Study

Author

Israel, Samuel, primary, Rusch, Sarah, additional, DeVincenzo, John, additional, Boyers, Alison, additional, Fok-Seang, Juin, additional, Huntjens, Dymphy, additional, Lounis, Nacer, additional, Mariёn, Kris, additional, Stevens, Marita, additional, and Verloes, René, additional

Published
2016
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28. 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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29. Respiratory Syncytial Virus Kinetics and Medical Resources Utilization in Hospitalized Infants and Children in Japan

Author

Tetsuka, Nobuyuki, primary, Tomita, Kentaro, additional, Matsumura, Kazuya, additional, Shinjoh, Masayoshi, additional, Kimura, Tomomi, additional, Ispas, Gabriela, additional, Ito, Kenta, additional, Mizuguchi, Koichi, additional, Funaki, Takanori, additional, Furuichi, Munehiro, additional, Nakagawa, Hidenori, additional, Rusch, Sarah, additional, Lounis, Nacer, additional, Houtmeyers, Els, additional, Bollekens, Jacques, additional, Shishido, Akira, additional, Nakayama, Yoshikazu, additional, Goto, Schoichiro, additional, Takahashi, Takao, additional, Sugaya, Norio, additional, and Miyairi, Isao, additional

Published
2015
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31. Novel Antibiotics Targeting Respiratory ATP Synthesis in Gram-Positive Pathogenic Bacteria

Author

Balemans, Wendy, primary, Vranckx, Luc, additional, Lounis, Nacer, additional, Pop, Ovidiu, additional, Guillemont, Jérôme, additional, Vergauwen, Karen, additional, Mol, Selena, additional, Gilissen, Ron, additional, Motte, Magali, additional, Lançois, David, additional, De Bolle, Miguel, additional, Bonroy, Kristien, additional, Lill, Holger, additional, Andries, Koen, additional, Bald, Dirk, additional, and Koul, Anil, additional

Published
2012
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46. Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline.

Author

Andries, Koen, Villellas, Cristina, Coeck, Nele, Thys, Kim, Gevers, Tom, Vranckx, Luc, Lounis, Nacer, de Jong, Bouke C., and Koul, Anil

Subjects
MYCOBACTERIUM tuberculosis, MICROBIOLOGY, MULTIDRUG-resistant tuberculosis, RESERPINE, PHARMACOLOGY, DISEASE susceptibility
Abstract

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications. [ABSTRACT FROM AUTHOR]

Published
2014
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49. Fluoroquinolone-Containing Third-Line Regimen against Mycobacterium tuberculosisIn Vivo

Author

Veziris, Nicolas, Truffot-Pernot, Chantal, Aubry, Alexandra, Jarlier, Vincent, and Lounis, Nacer

Abstract

ABSTRACTThe objective of the present study was to compare the activities of a third-line regimen recommended by the World Health Organization (WHO) and two derivatives of that regimen with the activity of the standard combination of isoniazid, rifampin, and pyrazinamide as a positive control against Mycobacterium tuberculosisin a murine model. The WHO regimen combines ofloxacin (OFX), ethionamide, amikacin, and pyrazinamide; in the two derivatives of this regimen, OFX was replaced by levofloxacin (LVX) or moxifloxacin (MXF). The four drugs, a fluoroquinolone (either OFX, LVX, or MXF), ethionamide, pyrazinamide, and amikacin, were administered for the first 2 months (initial phase); and two drugs, a fluoroquinolone (either OFX, LVX, or MXF) and ethionamide, were administered for the following 10 months (continuation phase). After 6 months of treatment, only the spleens and lungs of mice treated with the standard regimen became culture negative. From 9 months onward, all of the organs of mice treated with the MXF-containing third-line regimen were culture negative. The majority of organs from mice treated with the OFX-containing regimen continued to be culture positive, and the mean CFU counts remained unchanged for as long as 12 months. The results for mice treated with the LVX-containing regimen fell between those for the groups receiving the MXF- and OFX-containing regimens. In conclusion, the activity of the OFX-containing third-line regimen against M. tuberculosiswas rather weak in vivo, whereas when OFX was replaced by MXF, 9 months of treatment with a modified third-line regimen displayed bactericidal activity comparable to that of 6 months of treatment with the standard regimen in mice. The MXF-containing third-line regimen seems to be a powerful alternative for the treatment of tuberculosis (TB) when isoniazid and rifampin cannot be used, which is the main feature of multidrug-resistant TB.

Published
2003
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50. Effectiveness of Once-Weekly Rifapentine and Moxifloxacin Regimens against Mycobacterium tuberculosisin Mice

Author

Lounis, Nacer, Bentoucha, Abdelhalim, Truffot-Pernot, Chantal, Ji, Baohong, O'Brien, Richard J., Vernon, Andrew, Roscigno, Giorgio, and Grosset, Jacques

Abstract

ABSTRACTMice infected with 1.6 × 107CFU ofMycobacterium tuberculosiswere treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.

Published
2001
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