The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index; none of the 14 sources its claims cite is checked for support yet.
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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“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.
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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.
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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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“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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“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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 3
- 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.
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Probably 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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“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.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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“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.
plainSingle case- Asserted: passes — The authors put it forward as true.
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“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.
plaindirect- Asserted: passes — The authors put it forward as true.
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“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.
plainconditionaln = 36- Asserted: passes — The authors put it forward as true.
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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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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.
boosteddirect- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
hedged- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plain- Asserted: passes — The authors put it forward as true.
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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.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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]
Citations
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The Need for New Drugs against Tuberculosis
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THE F0F1-TYPE ATP SYNTHASES OF BACTERIA: Structure and Function of the F0 Complex
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Intracellular pH regulation by Mycobacterium smegmatis and Mycobacterium bovis BCG
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Synthesis and anti-tubercular evaluation of 4-quinolylhydrazones
Savini, L., Chiasserini, L., Gaeta, A., & Pellerano, C. (2002) · Bioorganic & Medicinal Chemistry · doi:10.1016/s0968-0896(02)00071-8 · Cited by 134
Cited by
Sorted by citations
Items 501–600 of 2,159
Zhang, Y., Chen, W., Jia, X., et al. (2019) · Chemical Communications · doi:10.1039/c8cc10235j · Cited by 63
Rodrigues, L., Cravo, P., & Viveiros, M. (2020) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2020.1760845 · Cited by 65
“which targets the mycobacterial ATP synthase, another oxidative phosphorylation component [61].”
BackgroundBattaglia, S., Spitaleri, A., Cabibbe, A. M., et al. (2020) · Journal of Clinical Microbiology · doi:10.1128/jcm.01304-20 · Cited by 63
“Mutations in the cellular target of BDQ, the C subunit of ATP synthase encoded by the atpE (rv1305) gene, have been associated with phenotypic resistance (23).”
BackgroundRecent Progress and Challenges for Drug-Resistant Tuberculosis Treatment
Stephanie, F., Saragih, M., & Tambunan, U. S. F. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13050592 · Cited by 65
Conformationally-constrained indeno[2,1-c]quinolines – a new class of anti-mycobacterial agents
Upadhayaya, R. S., Lahore, S. V., Sayyed, A. Y., et al. (2010) · Organic & Biomolecular Chemistry · doi:10.1039/b924102g · Cited by 63
Singh, S., Roy, K. K., Khan, S. R., Kashyap, V. K., Sharma, A., Jaiswal, S., Sharma, S., Krishnan, M. Y., Chaturvedi, V., Lal, J., et al. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.12.060 · Cited by 67
Drug development against tuberculosis: Impact of alkaloids
Mishra, S. K., Tripathi, G., Kishore, N., Singh, R. K., Singh, A. K., & Tiwari, V. K. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.06.005 · Cited by 67
Gomes, M. G. M., Rodrigues, P., Hilker, F. M., et al. (2007) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2007.06.005 · Cited by 63
“These caveats have motivated research into the development of therapeutic vaccines that could block reactivation and simultaneously reduce the risk of reinfection (Andries et al., 2005; Ha et al., 2003, 2005; Lowrie et al., 1999; Malowany et al., 2006; McShane et al., 2004).”
Panas, M. W., Jain, P., Yang, H., Mitra, S., Biswas, D., Wattam, A. R., Letvin, N. L., & Jacobs, W. R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414207111 · Cited by 62
A New Type of Na+-Driven ATP Synthase Membrane Rotor with a Two-Carboxylate Ion-Coupling Motif
Schulz, S., Cans, M. C. I., Krah, A., Yıldız, Ö., Leone, V., Matthies, D., Cook, G. M., Faraldo‐Gómez, J. D., & Meier, T. W. (2013) · PLoS Biology · doi:10.1371/journal.pbio.1001596 · Cited by 62
“tuberculosis c-ring can be inhibited by diarylquinolines, a new class of antibiotic compounds against multi-drug resistant strains [42,43].”
BackgroundEssential Metabolites of Mycobacterium tuberculosis and Their Mimics
Lamichhane, G., Freundlich, J. S., Ekins, S., Wickramaratne, N. A., Nolan, S. T., & Bishai, W. R. (2011) · mBio · doi:10.1128/mbio.00301-10 · Cited by 60
Sensitive, specific polymorphism discovery in bacteria using massively parallel sequencing
Nusbaum, C., Ohsumi, T. K., Gomez, J. E., Aquadro, J. A., Victor, T. C., Warren, R. M., Hung, D. T., Birren, B. W., Lander, E. S., & Jaffe, D. B. (2008) · Nature Methods · doi:10.1038/nmeth.1286 · Cited by 62
Prospects for the Future Using Genomics and Proteomics in Clinical Microbiology
Fournier, P., & Raoult, D. (2010) · Annual Review of Microbiology · doi:10.1146/annurev-micro-090110-102922 · Cited by 62
Biological Properties of 1H-1,2,3- and 2H-1,2,3-Triazoles
da Silva, F. D. C., Cardoso, M. F. D. C., Ferreira, P. G., & Ferreira, V. F. (2014) · Topics in heterocyclic chemistry · doi:10.1007/7081_2014_124 · Cited by 65
Targeting the ATP synthase in bacterial and fungal pathogens: beyond Mycobacterium tuberculosis
Vestergaard, M. R., Bald, D., & Ingmer, H. (2022) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2022.01.026 · Cited by 62
Musioł, R., Tabak, D., Niedbala, H., Podeszwa, B., Jampílek, J., Kráľová, K., Dohnal, J., Finster, J., Mencel, A., & Polański, J. (2008) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.02.065 · Cited by 62
Emerging Drugs for Active Tuberculosis
Ginsberg, A. M. (2008) · Seminars in Respiratory and Critical Care Medicine · doi:10.1055/s-0028-1085706 · Cited by 62
Birkenstock, T. A., Liebeke, M., Winstel, V., Krismer, B., Gekeler, C., Niemiec, M. J., Bisswanger, H., Lalk, M., & Peschel, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.288894 · Cited by 62
“salicylate (3), and fluoropyruvate (4).”
BackgroundResultThe chemical biology of new drugs in the development for tuberculosis
Barry, C. E., & Blanchard, J. S. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.04.008 · Cited by 61
Svensson, E. M., & Karlsson, M. O. (2017) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkx317 · Cited by 60
Htoo, H. H., Brumage, L., Chaikeeratisak, V., Tsunemoto, H., Sugie, J., Tribuddharat, C., Pogliano, J., & Nonejuie, P. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02310-18 · Cited by 58
“These screens resulted in the discovery of many antibiotics exhibiting both broad spectrum, such as streptomycin (19), and mycobacterium-specific activity, including isoniazid, pyrazinamide, ethionamide, ethambutol (4), and bedaquiline (20).”
BackgroundTBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus
Sarathy, J. P., Ganapathy, U. S., Zimmerman, M., Dartois, V. A., Gengenbacher, M., & Dick, T. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02404-19 · Cited by 64
“1) is a first-in-class diarylquinoline (DARQ) (30) 77 used for the treatment of multi-drug resistant tuberculosis (31, 32).”
InfluentialChemical sensor systems based on 2D and thin film materials
Mackin, C., Fasoli, A., Xue, M., Lin, Y. C., Adebiyi, A., Bozano, L. D., & Palacios, T. (2020) · 2D Materials · doi:10.1088/2053-1583/ab6e88 · Cited by 60
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Wade, M. M., & Zhang, Y. (2006) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkl358 · Cited by 61
“The new TB drug candidate diarylquinoline, which inhibits proton-ATPase just like DCCD, could also synergize with pyrazinamide activity.(14) In the present study, additional energy inhibitors CCCP, DNP, KCN and valinomycin were tested and CCCP and DNP were found to enhance pyrazinamide activity primarily for old cultu…”
BackgroundReduced susceptibility and resistance to bedaquiline in clinical M. tuberculosis isolates
Peretokina, I. V., Krylova, L. Y., Antonova, O. V., Kholina, M. S., Kulagina, E. V., Nosova, E. Y., Сафонова, С. Г., Borisov, S. E., & Zimenkov, D. V. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.01.007 · Cited by 62
Antibiotics and resistance: the two-sided coin of the mycobacterial cell wall
Batt, S. M., Burke, C., Moorey, A. R., & Besra, G. S. (2020) · The Cell Surface · doi:10.1016/j.tcsw.2020.100044 · Cited by 63
Safarian, S., Opel‐Reading, H. K., Wu, D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25537-z · Cited by 60
The application of next-generation sequencing technologies to drug discovery and development
Woollard, P. M., Mehta, N., Vamathevan, J. J., Horn, S. V., Bonde, B. K., & Dow, D. J. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.03.006 · Cited by 60
Lounis, N., Gevers, T., Berg, J. V. D., & Andries, K. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00566-08 · Cited by 60
Self-citationKim, D. H., Jhun, B. W., Moon, S. M., et al. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00665-19 · Cited by 60
Wang, Z., Soni, V., Marriner, G. A., Kaneko, T., Boshoff, H. I., Barry, C. E., & Rhee, K. Y. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1907946116 · Cited by 65
“BDQ exhibits bactericidal activity against Mtb in vitro, in mouse models of pulmonary TB, and in patients when given for either 2 or 6 mo in combination with a background regimen with multidrugresistant TB (9, 12).”
BackgroundBedaquiline inhibits the yeast and human mitochondrial ATP synthases
Luo, M., Zhou, W., Patel, H., Srivastava, A. P., Symersky, J., Bonar, M. M., Faraldo‐Gómez, J. D., Liao, M., & Mueller, D. M. (2020) · Communications Biology · doi:10.1038/s42003-020-01173-z · Cited by 66
Comprehensive review on mechanism of action, resistance and evolution of antimycobacterial drugs
Chauhan, A., Kumar, M., Kumar, A., & Kanchan, K. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119301 · Cited by 66
SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development
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How to cope with the quest for new antibiotics
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Bedaquiline and delamanid in tuberculosis
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“We reported the case of a 12-year-old Italian boy with laryngeal and pulmonary XDR-TB successfully treated with the compassionate use of delamanid, after having consulted the TB Consilium platform [91].”
BackgroundInfluentialIn Vitro Susceptibility Testing of Bedaquiline against Mycobacterium abscessus Complex
Brown‐Elliott, B. A., & Wallace, R. J. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01919-18 · Cited by 59
“intracellulare is associated with a nonsynonymous mutation in the atpE gene or in one of multiple nonsynonymous mutations of the efflux repressor gene mmpT5 (19, 20).”
BackgroundJi, B., Chauffour, A., Andries, K., et al. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.50.4.1558-1560.2006 · Cited by 59
“Dosages were as follows: R207910, 25 or 100 mg/kg of body weight (2); PA-824 (10, 16) and linezolid (5), 100 mg/kg; moxifloxacin, 150 mg/kg (4); rifampin and rifapentine, 10 mg/kg (4); and minocycline, 25 mg/kg (4).”
BackgroundSelf-citationAhmad, Z., & Laughlin, T. F. (2010) · Current Medicinal Chemistry · doi:10.2174/092986710791859270 · Cited by 59
“It is interesting that two mutations, D32A and A63P, in the c-subunit of mycobacterium ATP synthase confer resistance to diarylquinoline, a tuberculosis drug [63, 64].”
BackgroundKaniga, K., Hasan, R., Jou, R., et al. (2021) · Journal of Clinical Microbiology · doi:10.1128/jcm.02919-20 · Cited by 58
“tuberculosis (6), is indicated as part of combination therapy in adult and pediatric”
Singh, R., Manna, S., Nandanwar, H. S., & Purohit, R. (2023) · Microbes and Infection · doi:10.1016/j.micinf.2023.105279 · Cited by 59
Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research
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“This has been fueled primarily by the success of bedaquiline (BDQ), a diarylquinoline that inhibits the mycobacterial ATP synthase (4) and is approved for clinical use against multidrug-resistant (MDR) TB (5).”
BackgroundThe Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs
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“Examples are the novel anti-TB drug bedaquiline which targets ATP synthase (Andries et al., 2005) and the clinical candidate Q203 which intercepts the mycobacterial cytochrome bc1-aa3 supercomplex (Kalia et al.”
BackgroundATP Synthase Inhibition of Mycobacterium avium Is Not Bactericidal
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Background
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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