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A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis
Open accessAbstract
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 mug/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 dose 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.
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“R207910 was extensively distributed to tissues, including lungs and spleen (Fig. 3A, table S4).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“These average concentrations were greater than that achieving optimal activity in established infection in mice.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
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In the paper
“Low MICs were also found for other mycobacterial species, including Mycobacterium bovis, Mycobacterium kansasii and Mycobacterium ulcerans, as well as species naturally resistant to many other anti-TB agents and involved in opportunistic infections, such as Mycobacterium avium complex (MAC), Mycobacterium abscessus, Mycobacterium fortuitum and Mycobacterium marinum (Table 1).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“At 25 mg/kg, the activity of R207910 was significantly better than at 12.5 mg/kg (P = 0.005).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The bactericidal activity obtained by the RHZ combination after 2 months of therapy was matched by the combinations JHZ and RJZ after just 1 month of therapy.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
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In the paper
“Importantly, at 12.5 and 25 mg/kg, R207910 was significantly more active (P = 0.005) than 25 mg/kg isoniazid, a drug known for its strong, early bactericidal activity (Fig. 4A).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the susceptibility of R207910-resistant M. tuberculosis strains remained unchanged to other anti-TB agents, including isoniazid, rifampin, streptomycin, amikacin, ethambutol and moxifloxacin.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“To date, 20 molecules of the DARQ series have a minimum inhibitory concentration (MIC) below 0.5 µg/ml against M. tuberculosis H37Rv.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Data from a multiple-ascending-dose study have shown an increase (approximately by a factor of two) in AUC 0-24h from Day 1 to Day 14 of once-daily dosing at 50, 150 and 400 mg R207910, without substantial variation between subjects.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
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In the paper
“Plasma levels associated with efficacy in mice are well tolerated in healthy human volunteers.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
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- It may state two separate claims as one. 40
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In the paper
“The most active compound of the class, R207910, is a pure enantiomer with two chiral centers.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“No accumulation of R207910 was observed after five daily oral doses, indicating that slow redistribution from tissues contributed to the relatively long half-lives in plasma.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“In the second study, the good tolerability was maintained; only one subject withdrew from the study, because of a urinary tract infection (unrelated to R207910) after seven doses at 150 mg/day.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“When added to the first-line triple TB therapy combination RHZ, 25 mg/kg R207910 (J) increased the drop in bacterial load in the lungs by 2 log 10 after 1 month of therapy compared with standard RHZ treatment regimen, and a further 1 log 10 drop after 2 months.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
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In the paper
“Maximum plasma concentrations (C max ) of 0.40-0.54µg/ml with a single 6.25 mg/kg/dose were achieved within 1 hour and 1.1-1.3µg/ml with a 25 mg/kg/dose within 2-4 hours.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“The majority of adverse events reported (supporting online text), were considered possibly related to the study medication-placebo (seven of 18 subjects) or R207910 (20 of 36 subjects).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
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“The AUC showed a better correlation with the dose than C max , reflecting limitations in rate of absorption at higher dosing regimens, as confirmed in a single-dose pharmacokinetic study comparing C max and AUC after 6.25, 25 and 100 mg/kg.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“This anti-mycobacterial-specific spectrum differs from that of isoniazid, which has very poor activity against MAC.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
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In the paper
“In studies using oral treatment of R207910 for 5 days per week for 4 weeks, starting the day after inoculation, the minimal dose of R207910 that prevented mortality in nonestablished infection was 1.5 mg/kg, and the minimal effective dose (MED) preventing gross lung lesions was 6.5 mg/kg.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
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In the paper
“Exposure of M. tuberculosis in log-phase growth to concentrations of R207910 at 10-fold MIC resulted in a 3 log 10 reduction in bacterial counts after 12 days, indicating that R207910 has bactericidal activity in vitro (table S2).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Complementation studies have verified that the mutant atpE gene is responsible for resistance to R207910, implying that the atpE gene product is the target of R207910 in mycobacteria.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“The range of MICs for the international reference strain M. tuberculosis H37Rv and six fully antibiotic susceptible isolates was 0.03-0.120µg/ml (Table 1), versus 0.500 µg/ml for rifampin and 0.120 µg/ml for isoniazid (results not shown).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“All 30 isolates of MDR-TB tested were susceptible to 0.100 µg/ml of R207910, and 17 (57%) were susceptible to 0.010 µg/ml of R207910 (Table 2).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Pharmacokinetic results from the single-ascending-dose study suggested that R207910 is well absorbed after single oral administration, and the peak concentration was reached at 5 hours (median value) post-dose.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“R207910 had much higher MICs for Corynebacterium and Helicobacter pylori (MIC 4.0 µg/ml), and especially for other organisms such as Gram-positive Nocardia, Streptococcus pneumoniae, Staphylococcus aureus and Enterococcus faecalis, or Gram-negative Escherichia coli and Haemophilus influenzae (table S1).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Half-lives ranged from 43.7 to 64 hours in plasma and 28.1 to 92 hours in tissues (table S4).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Substitution of drugs included in the World Health Organization's firstline tuberculosis treatment regimen (rifampin, isoniazid and pyrazinamide) with R207910 accelerates bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“The DARQ R207910 is a member of a new chemical class of anti-mycobacterial agents and has an MIC equal to or lower than that of reference compounds.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“A single dose of 50 mg/kg R207910 in the non-established infection murine model of TB infection resulted in a bacteriostatic effect (0.5 log 10 drop in bacterial count in the lungs), which lasted for 8 days-a similar effect to that of rifapentine (10 mg/kg) (Fig. 3B).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“In established infection (treatment beginning 12-14 days after inoculation when bacterial load was 5.94 log 10 CFU), 25 mg/kg R207910 as monotherapy was at least as active as the triple combination therapy (rifampin [R] + isoniazid [H] + pyrazinamide [Z]), and more active than rifampin alone (Fig. 4B).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (MIC 0.06 µg/ml).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“The mean AUC 0-24h values were 7.91, 24 and 52 µg/hour/ml at steady state, corresponding to average concentrations of 0.33, 1.0 and 2.2 µg/ml across a dosing interval, with 50, 150 and 400 mg/day, respectively.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“The pharmacokinetics of R207910 were linear up to the highest dose tested (700 mg); both C max and AUC increased proportionally with the administered dose.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“The two point mutations identified (D32V for M. smegmatis and A63P for M. tuberculosis) are both in the membrane-spanning domain region of the protein.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“Areas under the concentration-time curve (AUCs) ranged from 5.0 to 5.9 µg/hour/ml with a 6.25 mg/kg/dose and 18.5 to 19.4 µg/hour/ml with a 25 mg/kg/dose (table S4).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
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In the paper
“From selection experiments, the proportion of resistant mutants that emerged was 5 x 10 -7 and 2 x 10 -8 at four-fold MIC, and 5 x 10 -8 and 1 x 10 -8 at eight-fold MIC for M. tuberculosis and M. smegmatis, respectively (8).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
What the sources say
- Not matchedcites [8] 8. Details of materials and methods and supporting online text are available as supporting material on Science Online.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
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In the paper
“Substitution of each of the three first-line drugs with R207910 resulted in a dramatic increase in potency, leading to complete culture conversion of the lungs in some animals after only 2 months of treatment.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“R207910 has potent early bactericidal activity in the nonestablished murine TB model, matching or exceeding that of isoniazid (Fig. 4A), which is consistent with in vitro observations pointing to a bactericidal activity.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, the bactericidal potency seen upon administration of a single dose of 100 mg/kg R207910 in vivo was similar to the effect seen upon continuous exposure of cultures to 0.6 µg/ml (or 10-fold the median MIC of the H37Rv strain) in vitro, giving a first indication of the pharmacodynamics of R207910.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the minimal bactericidal dose was very close to the MED, a finding confirming timedependent, rather than concentration-dependent, activity of R207910 in vitro.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Pharmacodynamic studies in mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Data suggest that maintaining average plasma levels of 0.3 µg/ml/day across a dosing interval, which is achieved with a 100 mg/kg/week dose, is necessary to achieve optimal effect of monotherapy in mice infected with strain H37Rv.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The killing effect was not increased by higher concentrations of the compound, suggesting the killing was time-dependent rather than concentration-dependent.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Although current first-line anti-TB drug regimens can achieve more than 99% efficacy, this is often reduced because of drug resistance (5).”
What the sources say
- Not matchedcites [5] 5. R. J. O'Brien, P. P. Nunn, Am. J. Respir. Crit. Care Med. 163, 1055 (2001).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Structurally and mechanistically, DARQs are very different from both fluoroquinolones (including methoxyquinolones) and other quinoline classes, including mefloquine and its analogs 4-methylquinolines and 4quinolylhydrazones (9-13).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
What the sources say
- Not matchedcites [9] 9. R. Jain, B. Vaitilingam, A. Nayyar, P. B. Palde, Bioorg. Med. Chem. Lett. 13, 1051 (2003).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10] 10. C. M. Kunin, W. Y. Ellis, Antimicrob. Agents Chemother. 44, 848 (2000).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [11] 11. M. R. Barbachyn, S. J. Brickner, Patent (International Publication Number: WO 93/09103, International Publication Date: 13 May, 1993, International Application Number: PCT/US92/08267, International Filing Date: 1992).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12] 12. L. Savini, L. Chiasserini, A. Gaeta, C. Pellerano, Bioorg. Med. Chem. 10, 2193 (2002). / www.sciencexpress.org /9 December 2004 / Page 4/ 10.1126/science.1106753
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13] 13. S. Vangapandu, M. Jain, R. Jain, S. Kaur, P. P. Singh, Bioorg. Med. Chem. 12, 2501 (2004).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The long half-lives and consequently prolonged exposure are important factors determining the duration of activity in vivo and provide a rationale for less frequent dosing regimens.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Chemistry and in vitro anti-mycobacterial activity.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A comparison of the sequences of ATP synthases of different bacteria and of eukaryotic ATP synthase provides a rationale for the specificity of the antibacterial spectrum and, to a lesser extent, the safety profile of R207910.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the distinct target of R207910 means that there is no crossresistance with existing anti-TB drugs, and our studies verified it is as effective against MDR strains as it is against fully antibiotic-susceptible strains.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Inhibition of ATP synthase function may lead to ATP depletion and imbalance in pH homeostasis, both contributing to decreased survival (15,16).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
What the sources say
- Not matchedcites [15] 15. M. Rao, T. L. Streur, F. E. Aldwell, G. M. Cook, Microbiology 147, 1017 (2001).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [16] 16. G. Deckers-Hebestreit, K. Altendorf, Annu. Rev. Microbiol. 50, 791 (1996).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These are all attributes that are valuable for treatment of chronic infections and they may also be important for the development of simpler dosing regimens.”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The extent of bacterial load, the most effective drug combinations and treatment duration needed for sterilization are all similar in mice and humans (17).”
§ A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis > Safety and tolerability in humans.
What the sources say
- Not matchedcites [17] 17. E. L. Nuermberger et al., Am. J. Respir. Crit. Care Med. 169, 421 (2004).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
The paper relies on this without support.
No tuberculosis-specific drugs have been discovered in 40 years.
“Tuberculosis has been increasing significantly on a worldwide basis over the past decade, but no tuberculosisspecific drugs have been discovered in 40 years.”
The paper relies on this without support.
The murine TB model is predictive of human TB treatment outcomes.
“The extent of bacterial load, the most effective drug combinations and treatment duration needed for sterilization are all similar in mice and humans (17).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“TMC207 is bactericidal towards most species of mycobacteria (109), but is only bacteriostatic against M. avium (118) and M. smegmatis (Berney and Cook, unpublished data).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When mycobacterial cells (growing or non-growing) are treated with TMC207, time-dependent (not dose-dependent) killing is observed (109).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The most promising compounds clinically, the diarylquinolines, have been shown to target the F1Fo-ATP synthase and inhibit ATP synthesis (109, 111, 112).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“M. smegmatis was used for the initial compound screening that identified diarylquinoline (later named Bedaquiline) as a specific inhibitor of mycobacterial ATP synthase in 2005, which ended a 40-year dearth in anti-TB drug discovery (147).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [147]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Furthermore, Bedaquiline, the first new TB drug in 40 years, was discovered through an M. smegmatis screen.”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [147]
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Cited by
Sorted by citations
Items 1,401–1,500 of 2,159
Fraunfelter, V. M., Pugh, B. A., Williams, A. P. L., et al. (2023) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.3c00317 · Cited by 9
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“The development of new low toxic anti-mycobacterial agent to reduce the prevalence of drug-resistant TB is urgent worldwide (Andries et al., 2005).”
BackgroundA novel molecule with notable activity against multi-drug resistant tuberculosis
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“In recent years, two new TB drugs, bedaquiline (BDQ) and delamanid, were conditionally approved for treatment of MDR TB infections but are still undergoing phase III clinical evaluations (3, 4).”
BackgroundInhibitors of enzymes in the electron transport chain of Mycobacterium tuberculosis
Thompson, A. M., & Denny, W. A. (2019) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2019.05.001 · Cited by 11
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Tuberculosis multirresistentediez años después
Luna, J. A. C., Mendoza, G., & de Castro, F. R. (2021) · Medicina Clínica · doi:10.1016/j.medcli.2020.08.018 · Cited by 9
HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria
Ngan, J. Y. G., Pasunooti, S., Tse, W., Meng, W., Ngan, S. F. C., Jia, H., Lin, J., Ng, S. W., Jaafar, M. T., Cho, S. L. S., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2006717118 · Cited by 9
“The lack of killing efficacy observed with BDQ, previously shown to kill both actively replicating and nonreplicating mycobacteria (29), may be explained by the fact that this drug exerts a delayed killing (30) and that 5-d incubation may not be sufficient to observe significant killing of nonreplicating mycobacteria.”
BackgroundSrinivas, V., Ruiz, R. A., Pan, M., Immanuel, S. R. C., Peterson, E. J. R., & Baliga, N. S. (2021) · Cell Reports Methods · doi:10.1016/j.crmeth.2021.100123 · Cited by 12
“It is known that bedaquiline kills Mtb relatively slowly compared with other frontline drugs and could explain the discord between CFU and CVS within 72 h of treatment (Andries et al., 2005; Koul et al., 2007, 2008, 2014; Peterson et al., 2016).”
BackgroundOn the Mg2+ binding site of the ε subunit from bacterial F-type ATP synthases
Krah, A., & Takada, S. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.018 · Cited by 9
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“Second, the incorporation of 36% w/v 2-hydroxypropyl-β-cyclodextrin as an excipient allowed for enhanced solubility of the hydrophobic drug, as has been reported previously [37], allowing the concentration of BDQ in solution to reach 15 mg/mL.”
MethodMeena, L. S., Dhakate, S. R., & Sahare, P. D. (2012) · Biotechnology and Applied Biochemistry · doi:10.1002/bab.1043 · Cited by 9
Extensively Drug Resistant Tuberculosis(XDR-TB)
Narang, S. (2009) · Cited by 9
Zhang, C., Zheng, G., Xu, S., & Xu, D. H. (2012) · Journal of Computer Science and Technology · doi:10.1007/s11390-012-1219-y · Cited by 9
“[8] Andries K, Verhasselt P, Guillemont J, Gohlmann H W, Neefs J M, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, Williams P, de Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-Pernot C, Lounis N, Jarlier V.”
BackgroundSingh, R., Ramachandran, V., Shandil, R. K., Sharma, S., Khandelwal, S., Karmarkar, M., Kumar, N., Solapure, S. M., Saralaya, R., Nanduri, R., et al. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.05148-14 · Cited by 9
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“Bedaquiline (TMC207, Sirturo) is a diarylquinoline inhibitor of mycobacterial ATP synthetase [2].”
BackgroundInhibition of F1‐ ATP ase from Trypanosoma brucei by its regulatory protein inhibitor Tb IF 1
Gahura, O., Panicucci, B., Váchová, H., Walker, J. E., & Zı́ková, A. (2018) · FEBS Journal · doi:10.1111/febs.14672 · Cited by 7
“The F-ATPase in Mycobacterium 262 tuberculosis is an authenticated drug target for treatment of tuberculosis, and bedaquiline, an inhibitor of 263 the enzyme, is now in clinical use [35,36].”
BackgroundCheng, Y., Liu, Z., Liang, H., et al. (2019) · Molecules · doi:10.3390/molecules24102021 · Cited by 9
Raghunand, T. R., Bishai, W. R., & Chen, P. (2006) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2006.01.012 · Cited by 9
New drugs being developed for the treatment of tuberculosis
Doggrell, S. A. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.7.917 · Cited by 9
“This is very important as it gives further possibilities for good therapeutic combinations of drugs to treat TB as described in the animal studies [1].”
BackgroundElsayed, M. S. A. E., Salah, A., Elbadee, A. A., & Roshdy, T. M. (2022) · BMC Microbiology · doi:10.1186/s12866-022-02568-0 · Cited by 9
“tuberculosis H37Rv (locus Rv1305); the encoded protein is a target of the new antimycobacterial diarylquinoline R2079100 that shows a bactericidal effect on mycobacteria [45, 46].”
BackgroundVadankula, G. R., Nilkanth, V. V., Rizvi, A., Yandrapally, S., Agarwal, A., Chirra, H., Biswas, R., Arifuddin, M., Nema, V., Alvala, M., et al. (2024) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.4c00277 · Cited by 8
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Human F-ATP synthase as a drug target
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Contribution of telacebec to novel drug regimens in a murine tuberculosis model
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Systems biology and its impact on anti-infective drug development
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“duction of relatively simple perturbations include changes to the cellular environment, induction or repression of selected genes, and addition of small molecule inhibitors (see also Chapter 3) [ 21 , 22].”
BackgroundChasák, J., Oorts, L., Dak, M., Šlachtová, V., Bazgier, V., Berka, K., Vooght, L. D., Smiejkowska, N., Calster, K. V., Moll, L. V., et al. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117504 · Cited by 9
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“In 2006, Ji et al. demonstrated the antileprosy activity of BDQ administered orally, a new diarylquinoline which was also active against other mycobacteria such as M . tuberculosis [6,7].”
BackgroundSelf-citationYang, J., Ma, C., Liao, M.-L., et al. (2024) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.3c02851 · Cited by 8
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“Sequencing the genome of resistant microorganism should reveal mutations correlating to the drug selection [7].”
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“This approach led to the discovery of bedaquilin, one of the few recently introduced anti-TB drugs [14].”
BackgroundMulti-drug resistant tuberculosis, ten years later
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Navigating tuberculosis drug discovery with target-based screening
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“Clinically approved and preclinical tuberculosis drugs differentiated into their discovery by targeted and nontargeted screening approaches: CPZEN-45 [142], DC-159a [143], benzothiozinones [144], PNU-100480 [145], SQ-109 [146], AZD5847 [147], PA-824 [148], TMC-207 [149], OPC-67683 [150], linezolid [151], moxifloxacin…”
BackgroundDrug testing in mouse models of tuberculosis and nontuberculous mycobacterial infections
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“Sirturo® (bedaquiline), a diarylquinoline (DARQ) compound, is a new potent anti-tuberculosis drug which can block the proton pump of adenosine triphosphate synthase (ATPase) and subsequently disorder the energy metabolism of bacteria [2,3].”
BackgroundEffects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers
Healan, A. M., Salata, R. A., Griffiss, J. M., et al. (2018) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.639 · Cited by 8
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4H-1,3-Benzothiazin-4-one a Promising Class Against MDR/XDR-TB
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Clinical implications of the global multidrug-resistant tuberculosis epidemic
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“Bedaquiline, an inhibitor of mycobacterial F1Fo-ATP synthase that binds to the enzyme’s oligomeric c subunit of Fo protein (Andries et al., 2005; Koul et al., 2007; Preiss et al., 2015), has been approved by FDA for the treatment of drug-resistant M.”
BackgroundHow will next-generation sequencing contribute to the knowledge concerning Helicobacter pylori?
Engstrand, L. G. (2009) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2009.02962.x · Cited by 8
Lawn, S. D., Edwards, D., & Wood, R. (2007) · Future HIV Therapy · doi:10.2217/17469600.1.4.387 · Cited by 8
“Diarylquinolone targets the proton pump of ATP synthase [88] and has very potent in vitro activity against both drug-sensitive and multidrug-resistant TB (MDR-TB).”
BackgroundLocal control of pulmonary resistance and lung compliance in the canine lung
Coon, R. L., Rattenborg, C. C., & Kampine, J. P. (1975) · Journal of Applied Physiology · doi:10.1152/jappl.1975.39.4.580 · Cited by 8
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Novel tuberculosis combination regimens of two and three-months therapy durationPreprint
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Toward Mycobacterium tuberculosis Virulence Inhibition: Beyond Cell Wall
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Thiazole-Scaffold-Based Anti-tubercular Agents: A Review on Synthesis and Structural Modifications
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“23,24”
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Mitochondrial dysfunction induced by bedaquiline as an anti-Toxoplasma alternative
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Inhibitors of F 1 F 0 -ATP Synthase Enzymes for the Treatment of Tuberculosis and Cancer
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Pre-Clinical Tools for Predicting Drug Efficacy in Treatment of Tuberculosis
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“• Standardised approaches are needed in evaluating all drug combinations in an in vitro HFIM, where drug exposures and human pharmacokinetic profiles of the drug in the target site are simulated to evaluate the impact of these combinations for cell killing and the suppression of resistance [41].”
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“Antitubercular drugs include bedaquiline, an oral diarylquinoline with potent bactericidal and sterilising activity that works by inhibiting mycobacterial ATP synthase [5].”
BackgroundZhu, H., Chen, Q., Zhao, L., & Hu, P. (2023) · Nutrition and Cancer · doi:10.1080/01635581.2023.2180825 · Cited by 7
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“in vitro mutations unfit in vivo YES YES NO/Limited Mutations confined to in vitro mutants/ unfit in vivo Large katG deletions isoniazid resistance [24], rpoB deletions rifampicin resistance [25]; likely some in vitro atpE mutations bedaquiline resistance [26]”
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Ragunathan, P., Ng, P. S., Singh, S., Poh, W. H., Litty, D., Kalia, N. P., Larsson, S., Harikishore, A., Rice, S. A., Ingham, P. W., et al. (2023) · Microbiology Spectrum · doi:10.1128/spectrum.02282-23 · Cited by 7
“…F-ATP synthase inhibitors, including squaramides, dihydro pyrazolo[1,5a]pyrazin-4-ones, diaminoquinazolines, thiazolidinediones, chloroquinolines, tetrahydroquinolines, diaminopyrimidines, new BDQ-analogs, including TBAJ-587 and -876, reviewed in 5, as well as new compound targets (9, 13–16).”
BackgroundTwo-Component Signalling Systems of M. tuberculosis: Regulators of Pathogenicity and More
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Genetic Strategies for Identifying New Drug Targets
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Tuberculosis in the 21st century
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Bedaquiline susceptibility test for totally drug-resistant tuberculosis Mycobacterium tuberculosis
Jang, J., Jung, Y., Choi, J., Jung, H., & Ryoo, S. (2017) · The Journal of Microbiology · doi:10.1007/s12275-017-6630-1 · Cited by 7
“12 mg/L, considerably lower than those found in our study (Andries et al., 2005).”
BackgroundResultBedaquiline for the treatment of multidrug-resistant tuberculosis: another missed opportunity?
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“…metabolite (D-BDQ), phospholipidosis (PLD), plasma exposure, tissue distribution, dog Bedaquiline (BDQ, also known as SIRTURO™, TMC207, R207910) is a diarylquinoline drug with a unique mechanism of action, targeting the mycobacterial adenosine 50-triphosphate synthase (Andries et al. 2005).”
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Mycobacterial Pathogenomics and Evolution
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Metabolite Dysregulation by Pranlukast in Mycobacterium tuberculosis
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“Bedaquiline, a well-known anti-tubercular drug, inhibits ATP synthase that leads to depletion of ATP and disruption of pH homeostasis, thus affecting bacterial survival [24,25].”
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“At present, only a few drug candidates are in Phase II clinical trials, e.g., PA-824 [Stover et al., 2000] and TMC-207 [Andries et al., 2005] (Fig.”
BackgroundHIGH-THROUGHPUT, MASSIVELY PARALLEL DNA SEQUENCING TECHNOLOGY FOR THE ERA OF PERSONALIZED MEDICINE
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Metadata
- Authors
- Andries, K., Verhasselt, P., Guillemont, J., Göhlmann, H. W. H., Neefs, J.-M., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N., & Jarlier, V.
- Affiliations
- Johnson & Johnson (United Kingdom) (GB)
- Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
- Corresponding author
- Andries, Koen
- Lounis, Nacer
- Venue
- Science
- Published
- 2005-01-14
- Volume
- 307
- Issue
- 5707
- Pages
- 223-227
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2158658436
- Cited by
- 2,191
- References
- 13
- Citations by year
- 2026: 63 · 2025: 98 · 2024: 103 · 2023: 106 · 2022: 111 · 2021: 98 · 2020: 136 · 2019: 141 · 2018: 102 · 2017: 124 · 2016: 120 · 2015: 129 · 2014: 140 · 2013: 106 · 2012: 102
- FWCI
- 27.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- diarylquinolines, Mycobacterium tuberculosis, tuberculosis drug resistance, ATP synthase inhibition, proton pump, bactericidal activity, combination therapy, isoniazid
- MeSH terms
- Amino Acid Sequence, Animals, Antitubercular Agents, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Drug Therapy, Combination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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