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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 1,101–1,200 of 2,159
Identification and optimization of a new series of anti-tubercular quinazolinones
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“Bedaquiline (BDQ) is a speciesspecific inhibitor of the mycobacterial F1F0-type ATP synthase and is the first antibiotic to receive FDA approval for the treatment of tuberculosis in 40 years (2).”
BackgroundEgorova, A., Salina, E. G., & Makarov, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413317 · Cited by 21
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New drugs and regimens for treatment of TB
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Genetic Approaches to Facilitate Antibacterial Drug DevelopmentPreprint
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“1µL of 1µg/µl (2µL of 0.5µg/µl) trypsin (prepared in 50mM ammonium bicarbonate) was added and the solution was left overnight at 37◦C. 1µL of concentrated HCl was added and the solution was incubated at 37◦C for 20min before mixing and later centrifuged at 36,000 g for 30min.”
BackgroundMethodSrikrishna, G., Gupta, S., Dooley, K. E., et al. (2015) · Future Microbiology · doi:10.2217/fmb.15.56 · Cited by 19
Ball-milling synthesis of sulfonyl quinolines via coupling of haloquinolines with sulfonic acids
Liu, X., Wang, J.-Q., Ma, H., et al. (2021) · Green Chemistry · doi:10.1039/d1gc02015c · Cited by 19
Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB)
Lee, B. S., & Pethe, K. (2022) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2022.2030309 · Cited by 20
Nimmo, C., Ortiz, A. T., Tan, C. C. S., Pang, J., Acman, M., Millard, J., Padayatchi, N., Grant, A. D., O’Donnell, M. R., Pym, A. S., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01289-5 · Cited by 21
“The discovery of bedaqui-line, a diarylquinoline antimycobacterial active against ATP synthase, which is highly effective against Mycobacterium tuberculosis ( Mtb ) [4], was reported in 2004.”
BackgroundExploration of Piperidinols as Potential Antitubercular Agents
Abuhammad, A., Fullam, E., Bhakta, S., Russell, A. J., Morris, G. M., Finn, P. W., & Sim, E. (2014) · Molecules · doi:10.3390/molecules191016274 · Cited by 19
“Bedaquiline (TMC-207), which inhibits mycobacterial ATP synthase, was approved by the FDA as part of the treatment regimen for MDR-TB [7,8].”
MethodThe Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053
Albesa-Jové, D., Comino, N., Tersa, M., Mohorko, E., Urresti, S., Dainese, E., Chiarelli, L. R., Pasca, M. R., Manganelli, R., Makarov, V., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677039 · Cited by 19
“890(3)) of both mutants fitted with the atomic coordinates of the crystal structure of Rv2466c (Fig.”
BackgroundBedaquiline: Fallible Hope Against Drug Resistant Tuberculosis
Singh, P., KUMARI, R. R., & Lal, R. (2017) · Indian Journal of Microbiology · doi:10.1007/s12088-017-0674-0 · Cited by 19
“approved) namely bedaquiline (Sirturo) [11].”
BackgroundInfluentialZhou, W., & Faraldo‐Gómez, J. D. (2018) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2018.03.019 · Cited by 20
Boot, M., Commandeur, S., Subudhi, A. K., Bahira, M., Smith, T. C., Abdallah, A. M., van Gemert, M., Lelièvre, J., Ballell, L., Aldridge, B. B., et al. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00083-18 · Cited by 19
“Examples of these are diarylquinolines (bedaquiline) and the more recently discovered benzothiazinones (10, 11).”
BackgroundAdvances in the development of molecular genetic tools for Mycobacterium tuberculosis
Chhotaray, C., Tan, Y., Mugweru, J., Islam, M. M., Hameed, H. M. A., Wang, S., Lu, Z., Wang, C., Li, X., Tan, S., et al. (2018) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2018.06.003 · Cited by 17
Genetics and roadblocks of drug resistant tuberculosis
Perdigão, J., & Portugal, I. (2018) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2018.09.023 · Cited by 18
An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives
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Antituberculosis Activity of the Antimalaria Cytochrome bcc Oxidase Inhibitor SCR0911
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Nitrite modulates aminoglycoside tolerance by inhibiting cytochrome heme-copper oxidase in bacteria
Zhang, Y., Guo, K., Meng, Q., & Gao, H. (2020) · Communications Biology · doi:10.1038/s42003-020-0991-4 · Cited by 20
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“The urgent need to find new drugs to reduce the global burden of TB is much discussed in the present biomedical research.[5] Natural products and their semi synthetic derivatives can play a vital”
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Arthur, P. K., Amarh, V., Cramer, P., Arkaifie, G. B., Blessie, E. J., Fuseini, M.-S. N., Carilo, I., Yeboah, R., Asare, L., & Robertson, B. D. (2019) · Antibiotics · doi:10.3390/antibiotics8010004 · Cited by 19
“Notably, the diarylquinoline TMC207, which is an anti-tubercular drug, was identified using Mycobacterium smegmatis as a model organism [11].”
BackgroundGample, S. P., Agrawal, S., & Sarkar, D. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-45652-8 · Cited by 19
Gray, W. A., Waldorf, B., Rao, M. G., Stiles, B. L., Griffiss, J. M., Salata, R. A., & Blumer, J. L. (2019) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2019.07.023 · Cited by 19
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“Many proteins that are part of electron transport chain and AtP synthase are essential for Mtb survival and the latter is targeted by the antibiotic bedaquiline, used for MDR Mtb (Andries et al. 2005).”
Fountain, A. J., Waller, N. J. E., Cheung, C., Jowsey, W. J., Chrisp, M. T., Troll, M. A., Edelstein, P. H., Cook, G. M., McNeil, M. B., & Ramakrishnan, L. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2426827122 · Cited by 20
A review on anti‐tuberculosis peptides: Impact of peptide structure on anti‐tuberculosis activity
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“Therapeutic targeting of mycobacterial respiration holds significant clinical promise, as highlighted by the FDA approval of the inhibitors bedaquiline (inhibitor of F1Fo-ATP synthase) (Andries et al., 2005; Cox and Laessig, 2014), delamanid (Stover et al.”
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Field guide to Nath's research work on ATP synthesis and hydrolysis
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Potential Strategies for Increasing Drug-Discovery Productivity
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Investigation of the Essentiality of Glutamate Racemase in Mycobacterium smegmatis
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“tuberculosis that has been used successfully as a drug development surrogate for pathogenic mycobacteria (16).”
BackgroundFilling the Pipeline - New Drugs for an Old Disease
Stehr, M., Elamin, A. A., & Singh, M. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026613666131113152908 · Cited by 19
“Rifamycins induce cytochromes P450 enzymes in the liver, which interact with other TB drug candidates such as bedaquiline and with antiretroviral agents [12-17].”
BackgroundRevisiting the ‘Chemiosmotic Theory’: Coupled Transport of Anion and Proton for ATP Synthesis
Agarwal, B. (2014) · Bioenergetics Open access · doi:10.4172/2167-7662.1000e116 · Cited by 18
“This is therefore a most fundamental process in biology that also has numerous applications in health and disease [12,13].”
BackgroundHarris, K. K., Fay, A., Yan, H.-G., Kunwar, P., Socci, N. D., Pottabathini, N., Juventhala, R. R., Djaballah, H., & Glickman, M. S. (2014) · ACS Chemical Biology · doi:10.1021/cb500573z · Cited by 18
New synthetic approaches towards analogues of bedaquiline
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“Bedaquiline (BDQ), an inhibitor of bacterial F1/FO ATPsynthase (Andries et al., 2005), shows differential effects on rat liver mitochondria at opposing concentrations (Belosludtsev et al., 2019).”
BackgroundFrom Magic Mountain to Table Mountain
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Metabolic Perspectives on Persistence
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“…animal studies indicate that BDQ is capable of killing both replicating and nonreplicating M. tuberculosis as modeled in vitro by hypoxia and nutrient starvation, and in vivo in an established model of chronic infection, wherein activity manifests as an accelerated bactericidal activity (77 – 81).”
BackgroundKim, J. H., Kwon, O. J., Kim, Y. S., et al. (2019) · Respiratory Investigation · doi:10.1016/j.resinv.2019.08.004 · Cited by 18
Evaluation and management of patients with pulmonary nontuberculous mycobacterial infections
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Absolute configuration and structural features of R207910, a novel anti-tuberculosis agent
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Self-citationResponse of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203
Chauhan, P., van der Meulen, S. A., Caetano, J. M. S., Goojani, H. G., Botman, D., van Spanning, R. J. M., Lill, H., & Bald, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810331 · Cited by 17
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“Bedaquiline (BDQ), a novel oral diarylquinoline drug, had excellent efficacy against both drug susceptible and drug resistant MTB [3] and was recommended by WHO for the treatment of MDR [4].”
BackgroundXu, J., Li, D., Shi, J., Wang, B., Ge, F., Guo, Z., Mu, X., Nuermberger, E. L., & Lu, Y. (2023) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01532-22 · Cited by 16
“BDQ resistance is conferred by target mutations in the atpE gene (9), as well as by nontarget mutations in Rv0678 (10) and pepQ (11).”
BackgroundStructure of the bc 1 – cbb 3 respiratory supercomplex from Pseudomonas aeruginosa
Trani, J. M. D., Gheorghita, A. A., Turner, M., Brzezinski, P., Ädelroth, P., Vahidi, S., Howell, P. L., & Rubinstein, J. L. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307093120 · Cited by 17
Quinolines: A Promising Heterocyclic Scaffold for Cancer Therapeutics
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Treatment of Pulmonary Nontuberculous Mycobacterial Infections: Many Questions Remain
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Novel diagnostics and therapeutics for drug-resistant tuberculosis
Toosky, M., & Javid, B. (2014) · British Medical Bulletin · doi:10.1093/bmb/ldu011 · Cited by 17
“The molecular target for bedaquiline, the first of a new class of agents known as diarylquinolines, is the mycobacterial ATP synthase.(34) Not only did its discovery validate bacterial metabolism as a bona fide antibiotic target, but also that antibiotics could act on highly conserved targets that are in both bacteria…”
BackgroundCoxon, G. D., Cooper, C. B., Gillespie, S. H., et al. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis191 · Cited by 17
“However, unlike the lack of success in translating target activity into whole cell activity, there exist a number of techniques available to identify the sites of action, with noted successful examples of this approach [26].”
BackgroundTuberculosis Control: Challenges of an Ancient and Ongoing Epidemic
Cummings, K. J. (2007) · Public Health Reports · doi:10.1177/003335490712200517 · Cited by 17
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Two Decades of TB Drug Discovery Efforts—What Have We Learned?
Bandodkar, B., Shandil, R. K., Bhat, J. J., & Balganesh, T. S. (2020) · Applied Sciences · doi:10.3390/app10165704 · Cited by 17
“Bedaquiline, a non-competitive inhibitor of ATPS, is a front-line treatment for MDR TB [67,68].”
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“Whole-genome sequencing and a comparison of the resistant suppressors and sensitive strains revealed point mutations in the gene atpE, which encodes a protein in the F0 component of ATP synthase (Andries et al. 2005).”
BackgroundCrandall, P. G., Ricke, S. C., O’Bryan, C. A., & Parrish, N. M. (2012) · Journal of Environmental Science and Health Part B · doi:10.1080/03601234.2012.669331 · Cited by 17
“[ 11 – 13 ] Plant essential oils have been widely used throughout human history for a variety of medicinal and cosmetic purposes.”
BackgroundHeightened Vulnerability to MDR-TB Epidemics after Controlling Drug-Susceptible TB
Bishai, J. D., Bishai, W. R., & Bishai, D. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012843 · Cited by 17
“In addition, the model makes no provision for second-line drugs to treat MDR-TB or for the introduction of new drugs active against both drug-susceptible and MDR-TB [29,30,31,32].”
BackgroundFighting mycobacterial infections by antibiotics, phytochemicals and vaccines
Bamberger, D., Jantzer, N., Leidner, K., Arend, J., & Efferth, T. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.09.002 · Cited by 17
Targeting the role of N-terminal methionine processing enzymes in Mycobacterium tuberculosis
Olaleye, O. A., Bishai, W. R., & Liu, J. O. (2009) · Tuberculosis · doi:10.1016/s1472-9792(09)70013-7 · Cited by 17
On the ATP binding site of the ε subunit from bacterial F-type ATP synthases
Krah, A., & Takada, S. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.01.007 · Cited by 17
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QSAR based therapeutic management of M. tuberculosis
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“…Almeida Da Silva and Palomino (2011), Maus et al. (2005) 11 Bedaquiline (TMC207) Rv0678 Clinical trial phase III atpE ATP synthase Andries et al. (2014, 2005) 12 Delamanid (OPC-67683) RV3547 Clinical trial phase III ddn Hypothetical 16.4 kDa Manjunatha et al. (2006), O’Brien…”
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Identification of TB-E12 as a novel FtsZ inhibitor with anti-tuberculosis activity
Lin, Y., Zhang, H., Zhu, N., et al. (2018) · Tuberculosis · doi:10.1016/j.tube.2018.04.002 · Cited by 17
Modranka, J., Li, J., Parchina, A., Vanmeert, M., Dumbre, S. G., Salman, M., Myllykallio, H., Becker, H. F., Vanhoutte, R., Margamuljana, L., et al. (2019) · ChemMedChem · doi:10.1002/cmdc.201800739 · Cited by 17
Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery
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A systematic assessment of mycobacterial F1‐ATPase subunit ε’s role in latent ATPase hydrolysis
Wong, C. F., Lau, A., Harikishore, A., Saw, W. G., Shin, J. S., Ragunathan, P., Bhushan, S., Ngan, S. C., Sze, S. K., Bates, R. W., et al. (2020) · FEBS Journal · doi:10.1111/febs.15440 · Cited by 17
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“In this study, the genomes of three R207910-resistant pathogens were sequenced and comparative analysis conducted to identify point mutations that conferred resistance.”
MethodInfluentialPharmacodynamics and Bactericidal Activity of Bedaquiline in Pulmonary Tuberculosis
Lyons, M. A. (2021) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01636-21 · Cited by 16
“Bedaquiline is a mycobacterial ATP synthase inhibitor (9).”
BackgroundHughes, J. A., Solans, B. P., Draper, H. R., Schaaf, H. S., Winckler, J. L., van der Laan, L., Radtke, K. K., Fourie, B., Wiesner, L., Hesseling, A. C., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciac252 · Cited by 17
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Management of drug resistantTB in patients with HIV co-infection
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“Bedaquiline (also called TMC207 and R207910) belongs to the diarylquinoline group and was developed by Jannsen Pharmaceuticals Development (Titusville, NJ, USA).[68] Bedaquiline shows a quinolinic central heterocyclic nucleus with alcohol and amine side chains responsible for the antimycobacterial activity.”
BackgroundChemical Tools for Dissecting Bacterial Physiology and Virulence
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Synthetic investigational new drugs for the treatment of tuberculosis
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“The compound also exhibits a high bactericidal activity when used alone and in combination with standard first-line anti-TB drugs.[25]”
BackgroundCurrent strategies to treat tuberculosis
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New antituberculosis drugs targeting the respiratory chain
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Chemical Tools for Illumination of Tuberculosis Biology, Virulence Mechanisms, and Diagnosis
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Making Sense of Antisense in Antibiotic Drug Discovery
Wright, G. D. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2009.08.009 · Cited by 17
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“This approach has produced a large set of starting chemical points for anti-bacterial & anti-parasitic lead discovery [14,28–32].”
BackgroundThe pregnane X receptor in tuberculosis therapeutics
Shehu, A. I., Li, G., Xie, W., & Ma, X. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2016.1121381 · Cited by 16
“[75] Bedaquiline is more effective against the resistant strains of Mtb compared with wild-type strains.[75] Bedaquiline is metabolized by CYP3A4 to an N-desmethyl metabolite.”
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
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