Telacebec (Q203), a New Antituberculosis Agent

Jager, Veronique R. de; Dawson, Rodney; Niekerk, Christo van; Hutchings, Jane; Kim, Jeongjun; Vanker, Naadira; Merwe, Lize van der; Choi, Jin–Ho; Nam, Kiyean; Diacon, Andreas H.

doi:10.1056/nejmc1913327

Cited by 99 publications

(99 citation statements)

References 4 publications

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“…These results are in line with mouse PK results from Pethe et al (12) and, more importantly, comparable to the plasma C max and AUC 0 -∞ values of 0.38 g/ml and 6.3 g-h/ml, respectively, after a single dose of 100 mg in fed human (17) subjects. Considering that we observed dose-proportional PK in mice, Q203 doses of 2 to 10 mg/kg in mice likely correspond well to the daily doses of 100 to 300 mg that were recently reported to be well tolerated and safe in phase 1 trials and TB patients over 14 days of dosing in a recent phase 2a trial (22), provided that the drug is administered with food. Therefore, we predict that these doses can safely shorten the treatment of BU to 5 doses or less.…”

Section: Discussionsupporting

confidence: 77%

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Almeida

Converse

Omansen

et al. 2020

Antimicrob Agents Chemother

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Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

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Section: Discussionsupporting

confidence: 77%

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Almeida

Converse

Omansen

et al. 2020

Antimicrob Agents Chemother

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“…Between the two terminal oxidases, the Cyt‐ bcc:aa 3 is particularly vulnerable to chemical inhibition (Moraski et al , 2011; Abrahams et al , 2012; Moraski et al , 2013; Pethe et al , 2013; Rybniker et al , 2015; Moraski et al , 2016). The recent demonstration that the Cyt‐ bcc:aa 3 inhibitor Q203 is potent in the two‐week early bactericidal activity (EBA) proof‐of‐concept study in man provided another promising drug candidate for TB treatment (de Jager et al , 2020). However, we need to be cognizant that the potency of Q203 observed in an EBA study may not translate into treatment shortening unless the drug candidate is combined with appropriate companion drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Several preclinical‐stage drugs targeting the type II NADH dehydrogenases (Weinstein et al , 2005; Warman et al , 2013; Dunn et al , 2014), the cytochrome bcc:aa 3 (Moraski et al , 2011; Abrahams et al , 2012; Moraski et al , 2013; Pethe et al , 2013; Rybniker et al , 2015; Moraski et al , 2016), and menaquinone synthesis were discovered (Lu et al , 2008; Debnath et al , 2012; Lu et al , 2012). Telacebec (Q203), a drug candidate targeting the cytochrome bcc:aa 3 terminal oxidase (Pethe et al , 2013), recently demonstrated a favorable safety profile and potency in a phase 2 clinical trial (de Jager et al , 2020). Q203 binds to the cytochrome b subunit of the cytochrome bcc and is bacteriostatic in low nanomolar concentration (Pethe et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis

et al. 2020

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The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F 1 F 0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa 3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa 3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotictolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.

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“…In June 2019, Q203 passed the Phase 2a EBA (Early Bactericidal Activity) clinical trial (NCT03563599), showing promise for its use in therapy alone or in combination and bringing high hopes for the development of new optimized IPAs as a class of medicine. Currently, it is being evaluated for safety, tolerability, and pharmacokinetics [ 64 ].…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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Telacebec (Q203), a New Antituberculosis Agent

Cited by 99 publications

References 4 publications

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

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