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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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THE F0F1-TYPE ATP SYNTHASES OF BACTERIA: Structure and Function of the F0 Complex
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Flagged first, then by citations
Cited by
Sorted by citations
Items 301–400 of 2,159
Current perspectives in drug discovery against tuberculosis from natural products
Nguta, J. M., Appiah‐Opong, R., Nyarko, A. K., Yeboah‐Manu, D., & Addo, P. (2015) · International Journal of Mycobacteriology · doi:10.1016/j.ijmyco.2015.05.004 · Cited by 109
“Fortunately, advances in genome sequencing technology can perhaps augment the ‘ whole-cell-screening’ approaches since it can enable the identification of more targets [29,73].”
BackgroundDrugs in Development for Tuberculosis
Ginsberg, A. M. (2010) · Drugs · doi:10.2165/11538170-000000000-00000 · Cited by 104
“TMC207 is an inhibitor of the F0 subunit of themycobacterial adenosine triphosphate (ATP) synthase proton pump,([9,10]) a novel mechanism of action againstM.”
BackgroundMethodInfluentialLeads for antitubercular compounds from kinase inhibitor library screens
Magnet, S., Hartkoorn, R. C., Székely, R., Pató, J., Triccas, J. A., Schneider, P. A., Szántai-Kis, C., Őrfi, L., Chambon, M., Banfi, D., et al. (2010) · Tuberculosis · doi:10.1016/j.tube.2010.09.001 · Cited by 105
Succinate Dehydrogenase is the Regulator of Respiration in Mycobacterium tuberculosis
Hartman, T. E., Weinrick, B. C., Vilchèze, C., Berney, M., Tufariello, J. M., Cook, G. M., & Jacobs, W. R. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004510 · Cited by 104
“The recent FDA approval of Bedaquiline lends credence to the idea that non-replicating cells still remain susceptible to inhibitors targeting maintenance bioenergetics, albeit at a reduced rate compared to current effective drugs [8,58–60].”
ResultNew tuberculosis drugs on the horizon
Cole, S. T., & Riccardi, G. (2011) · Current Opinion in Microbiology · doi:10.1016/j.mib.2011.07.022 · Cited by 101
“The mode of action was identified through the isolation of drug-resistant spontaneous mutants harbouring alterations in the atpE gene, coding for the ATP synthase c subunit; particularly, changes at D32V and A63P were associated with resistance [20].”
BackgroundCruz, R. C. D. S., Bührer-Sékula, S., Penna, M. L. F., et al. (2017) · Anais Brasileiros de Dermatologia · doi:10.1590/abd1806-4841.20176724 · Cited by 104
Novel dihydropyrimidines as a potential new class of antitubercular agents
Trivedi, A. R., Bhuva, V. R., Dholariya, B. H., Dodiya, D. K., Kataria, V. B., & Shah, V. H. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.08.046 · Cited by 106
Antibacterial activity of long-chain fatty alcohols against mycobacteria
Mukherjee, K., Tribedi, P., Mukhopadhyay, B., & Sil, A. K. (2012) · FEMS Microbiology Letters · doi:10.1111/1574-6968.12043 · Cited by 103
“Membrane active agents generally have multiple target sites and diverse modes of action against the organism, reducing the chance of mutation at the target site (Andries et al., 2005; Koul et al., 2008).”
BackgroundNew tuberculosis drug leads from naturally occurring compounds
Quan, D. H., Nagalingam, G., Payne, R. J., & Triccas, J. A. (2017) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2016.12.024 · Cited by 107
Kondreddi, R. R., Jiřiček, J., Rao, S. P. S., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4012774 · Cited by 103
Perspective: Challenges and opportunities in TB drug discovery from phenotypic screening
Manjunatha, U. H., & Smith, P. W. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.12.031 · Cited by 103
Tuberculosis pharmacotherapy: strategies to optimize patient care
Mitnick, C. D., McGee, B., & Peloquin, C. A. (2009) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656560802694564 · Cited by 103
“[156] The target of TMC207 is the proton pump of adenosine triphosphate (ATP) synthase.”
BackgroundInfluentialXu, Z., Pupek, K., Suling, W. J., et al. (2006) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2006.02.017 · Cited by 102
Targeting bacterial energetics to produce new antimicrobials
Hards, K., & Cook, G. M. (2017) · Drug Resistance Updates · doi:10.1016/j.drup.2017.11.001 · Cited by 102
Tasneen, R., Tyagi, S. K., Williams, K. N., et al. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00686-08 · Cited by 101
“However, as substitution experiments have become a common method for evaluating whether a new drug may contribute additive activity to the existing first-line regimen (1, 9, 10, 12), caution should be exercised in interpreting the results of substituting a new drug for INH in the RIF-INH-PZA regimen unless the RIF-PZA…”
MethodSusceptibility Test Methods: Mycobacteria, Nocardia , and Other Actinomycetes
Woods, G. L., Lin, S.-Y. G., & Desmond, E. P. (2011) · Wiley eBooks · doi:10.1128/9781555816728.ch73 · Cited by 101
Singh, V., Donini, S., Pacitto, A., Sala, C., Hartkoorn, R. C., Dhar, N., Kéri, G., Ascher, D. B., Mondésert, G., Vocat, A., et al. (2016) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.6b00102 · Cited by 101
Mycobacterium tuberculosis : immune response, biomarkers, and therapeutic intervention
Li, Z., Yang, L., Li, L., Ye, Z., & Gong, W. (2024) · MedComm · doi:10.1002/mco2.419 · Cited by 123
Natural Products, Small Molecules, and Genetics in Tuberculosis Drug Development
Gutierrez‐Lugo, M., & Bewley, C. A. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm070719i · Cited by 101
Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X., & Andries, K. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.79 · Cited by 100
Self-citationNew anti-tuberculosis drugs and regimens: 2015 update
D’Ambrosio, L., Centis, R., Sotgiu, G., Pontali, E., Spanevello, A., & Migliori, G. B. (2015) · ERJ Open Research · doi:10.1183/23120541.00010-2015 · Cited by 99
Identification of KasA as the cellular target of an anti-tubercular scaffold
Abrahams, K. A., Chung, C., Ghidelli, S., Rullás, J., Rebollo-López, M. J., Gurcha, S. S., Cox, J. A. G., Mendoza-Losana, A., Jiménez‐Navarro, E., Martínez, M. S., et al. (2016) · Nature Communications · doi:10.1038/ncomms12581 · Cited by 97
Bedaquiline: Current status and future perspectives
Khoshnood, S., Goudarzi, M., Taki, E., Darbandi, A., Kouhsari, E., Heidary, M., Motahar, M., Moradi, M., & Bazyar, H. (2021) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2021.02.017 · Cited by 100
How Mycobacterium Tuberculosis goes to Sleep: The Dormancy Survival Regulator DosR a Decade Later
Boon, C., & Dick, T. (2012) · Future Microbiology · doi:10.2217/fmb.12.14 · Cited by 101
“It is notable that the new clinical candidate TMC207, a diarylquinoline ATP synthase inhibitor that kills dormant bacilli, showed very good efficacy in multidrug-resistant TB patients in a proof-of-concept study [33,34].”
BackgroundChallenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis
Machado, D., Girardini, M., Viveiros, M., & Pieroni, M. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.01367 · Cited by 99
“At this end, new technologies, including in vitro resistance mutation analysis (Andries et al., 2005; Manjunatha et al., 2006), knockout studies and construction of conditional mutants (Singh and Mizrahi, 2017), cytological profiling (Nonejuie et al.”
BackgroundMethodLiu, B., Gao, H., Yu, Y., et al. (2013) · The Journal of Organic Chemistry · doi:10.1021/jo401707j · Cited by 98
Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
Lee, B. S., Hards, K., Engelhart, C. A., Hasenoehrl, E., Kalia, N. P., Mackenzie, J. S., Sviriaeva, E. N., Chong, S. M. S., Manimekalai, M. S. S., Koh, V. H. Q., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202013207 · Cited by 98
Haagsma, A. C., Driessen, N. N., Hahn, M., Lill, H., & Bald, D. (2010) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2010.02123.x · Cited by 102
“In recent years, mycobacterial ATP synthase has been identified as the target of diarylquinolines, a new class of potent antimycobacterial drugs (Andries et al., 2005; Koul et al., 2007).”
BackgroundIn Vitro Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex
Brown‐Elliott, B. A., Philley, J. V., Griffith, D. E., Thakkar, F., & Wallace, R. J. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01798-16 · Cited by 97
Goldman, R. C. (2013) · Tuberculosis · doi:10.1016/j.tube.2013.09.003 · Cited by 94
Bayesian Models Leveraging Bioactivity and Cytotoxicity Information for Drug Discovery
Ekins, S., Reynolds, R. C., Kim, H., Koo, M.-S., Ekonomidis, M., Talaue, M. T., Paget, S. D., Woolhiser, L. K., Lenaerts, A. J. M., Bunin, B. A., et al. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.01.011 · Cited by 99
“Fortunately, one screen of the non-pathogenic Mycobacterium smegmatis unearthed a diarylquinoline hit that led to the clinical candidate bedaquiline (Andries et al., 2005), while another resulted in the early-phase candidate SQ109 (Lee et al., 2003).”
BackgroundQuinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents
Shirude, P. S., Paul, B., Choudhury, N. R., et al. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300134b · Cited by 97
Clinical value of whole-genome sequencing of Mycobacterium tuberculosis
Takiff, H. E., & Feo, O. (2015) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(15)00071-7 · Cited by 96
Svensson, E. M., Aweeka, F. T., Park, J., Marzan, F., Dooley, K. E., & Karlsson, M. O. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00191-13 · Cited by 98
“BDQ targets bacterial ATP synthase and disrupts energy metabolism (5, 6).”
BackgroundBedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?
Field, S. K. (2015) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622315582325 · Cited by 102
“Bedaquiline kills both dormant and actively replicating mycobacteria by inhibiting mycobacterial adenosine triphosphate (ATP) synthase, an essential membrane-bound enzyme, interfering with energy production and disrupting intracellular metabolism [Andries et al. 2005; Haagsma et al. 2011].”
BackgroundMethodInfluentialTang, J., Wang, B., Wu, T. S., Wan, J., Tu, Z., Njire, M. M., Wan, B., Franzblauc, S. G., Zhang, T., Lu, X., et al. (2015) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5b00176 · Cited by 96
Diacon, A. H., Dawson, R., von Groote-Bidlingmaier, F., et al. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02243-12 · Cited by 95
“Bedaquiline (BDQ), previously known as TMC207, is a new antituberculosis agent with a unique mechanism of action targeting ATP synthase (1).”
BackgroundStanley, S. A., Kawate, T., Iwase, N., Shimizu, M., Clatworthy, A. E., Kazyanskaya, E., Sacchettini, J. C., Ioerger, T. R., Siddiqi, N., Minami, S., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1302114110 · Cited by 95
“Generating resistance to an antibiotic followed by nextgeneration sequencing to identify the basis of resistance has been one useful approach to facilitate target identification of novel small molecules (2, 4).”
BackgroundBedaquiline – The first ATP synthase inhibitor against multi drug resistant tuberculosis
Lakshmanan, M., & Xavier, A. S. (2013) · Journal of Young Pharmacists · doi:10.1016/j.jyp.2013.12.002 · Cited by 94
Mu, S., Zhu, Y., Wang, Y., Qu, S., Huang, Y., Zheng, L., Duan, S., Yu, B., Qin, M., & Xu, F. (2022) · Advanced Materials · doi:10.1002/adma.202204065 · Cited by 93
Novel Antibiotics Targeting Respiratory ATP Synthesis in Gram-Positive Pathogenic Bacteria
Balemans, W., Vranckx, L., Lounis, N., Pop, O. I., Guillemont, J., Vergauwen, K., Mol, S., Gilissen, R., Motte, M., Lançois, D., et al. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00273-12 · Cited by 96
“1), a new clinical diarylquinoline drug candidate, is a highly efficient strategy for the treatment of drugresistant Mycobacterium tuberculosis (1, 24).”
BackgroundSelf-citationF1F0-ATP synthases of alkaliphilic bacteria: Lessons from their adaptations
Hicks, D. B., Liu, J., Fujisawa, M., & KRULWICH, T. A. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.02.028 · Cited by 102
Antimycobacterial activity of bacteriocins and their complexes with liposomes
Sosunov, V. V., Mischenko, V. V., Eruslanov, B. V., Ea, S., Shakina, Y. N., Stern, N. J., Majorov, K. B., Sorokoumova, G. M., Селищева, А. А., & Apt, A. S. (2007) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkm053 · Cited by 99
“Nevertheless, the search for antimycobacterial agents with distinct mechanisms of action should be continued.(6) It is well established that a specific class of peptides derived from diverse Gram-positive bacteria species—bacteriocins (Bcn)—exert activity against a wide range of bacteria.”
BackgroundFeng, J., Lupien, A., Gingras, H., Wasserscheid, J., Dewar, K., Légaré, D., & Ouellette, M. (2009) · Genome Research · doi:10.1101/gr.089342.108 · Cited by 93
“Discussion Complete bacterial genome sequencing is emerging as a cost effective approach for identifying candidate genes and determining the mode of action and resistance to drugs (Albert et al. 2005; Andries et al. 2005; Fournier et al. 2006; Howden et al. 2008; Manjunatha et al. 2006; Mwangi et al. 2007).”
BackgroundNew approaches in the diagnosis and treatment of latent tuberculosis infection
Ahmad, S. (2010) · Respiratory Research · doi:10.1186/1465-9921-11-169 · Cited by 94
“A diarylquinoline (R207910 also known as TMC207) has shown more potent early bactericidal activity than INH during early phase of infection and higher bactericidal activity late in infection than RMP alone and thus may provide another option for the treatment of LTBI [205,206].”
BackgroundGenetic requirements for Staphylococcus aureus nitric oxide resistance and virulence
Grosser, M. R., Paluscio, E., Thurlow, L. R., Dillon, M. M., Cooper, V. S., Kawula, T. H., & Richardson, A. R. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006907 · Cited by 94
“Importantly, there have been recent attempts to develop compounds that specifically target bacterial F 1 F 0 ATPases, including diarylquinolone drugs specific for the Mycobaterium tuberculosis F 1 F 0 ATPase that have been entered into phase IIb clinical trials[48,49].”
Richard, M., Gutiérrez, A. V., Viljoen, A. J., Rodriguez-Rincon, D., Roquet, F., Blaise, M., Everall, I., Parkhill, J., Floto, R. A., & Kremer, L. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01316-18 · Cited by 104
van Ingen, J., Ferro, B. E., Hoefsloot, W., Boeree, M. J., & van Soolingen, D. (2013) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.2013.830413 · Cited by 92
Cambau, E., Viveiros, M., Machado, D., et al. (2014) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dku438 · Cited by 91
Self-citationIonophoric effects of the antitubercular drug bedaquiline
Hards, K., McMillan, D. G. G., Schurig-Briccio, L. A., Gennis, R. B., Lill, H., Bald, D., & Cook, G. M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803723115 · Cited by 92
“BDQ is not reported to inhibit growth of nonmycobacterial strains (2) and in mammalian mitochondria the drug did not affect either ATP synthesis activity (10) or the membrane potential (11).”
BackgroundInfluentialDrug resistance mechanisms and novel drug targets for tuberculosis therapy
Islam, M. M., Hameed, H. M. A., Mugweru, J., Chhotaray, C., Wang, C., Tan, Y., Liu, J., Li, X., Tan, S., Ojima, I., et al. (2016) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2016.10.002 · Cited by 91
Multidrug-Resistant Tuberculosis
Nettleman, M. D. (2005) · JAMA · doi:10.1001/jama.293.22.2788 · Cited by 90
Gasse, C., Douguet, D., Huteau, V., Marchal, G., Munier‐Lehmann, H., & Pochet, S. (2008) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.04.045 · Cited by 90
Ganihigama, D. U., Sureram, S., Sangher, S., et al. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.10.026 · Cited by 90
Enfermedades Infecciosas y Microbiología Clínica
Viasus, D., Antón, A., Pumarola, T., & Carratalà, J. (2016) · Cited by 90
Alexander, D. C., Vasireddy, R., Vasireddy, S., Philley, J. V., Brown‐Elliott, B. A., Perry, B. J., Griffith, D. E., Benwill, J. L., Cameron, A. D. S., & Wallace, R. J. (2016) · Journal of Clinical Microbiology · doi:10.1128/jcm.02087-16 · Cited by 93
“Consistent with this, BDQ resistance was first associated with mutations in the atpE gene (8, 9).”
BackgroundLü, P., Asseri, A. H., Kremer, M., Maaskant, J. J., Ummels, R., Lill, H., & Bald, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-20989-8 · Cited by 92
Novel drugs against tuberculosis: a clinician's perspective
Olaru, I. D., von Groote-Bidlingmaier, F., Heyckendorf, J., et al. (2014) · European Respiratory Journal · doi:10.1183/09031936.00162314 · Cited by 89
Rising standards for tuberculosis drug development
Balganesh, T. S., Alzari, P. M., & Cole, S. T. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.08.001 · Cited by 89
In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis
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“One of those drugs is bedaquiline (1, 2, 3, 4), a diarylquinoline inhibitor of Mycobacterium tuberculosis ATP synthase and the other is delamanid (OPC-67683, Deltyba) (5), an antitubercular nitroimidazole.”
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“exception, the mycobacterial adenosine triphosphate synthase was identified as a novel drug target on the basis of genomic sequencing [9].”
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“activity against mycobacteria by inhibiting ATP synthase (8).”
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“Bedaquiline is a diarylquinoline compound with a novel mechanism of action that targets the ATP synthase (206).”
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“However, the combination of RIF and TMC207 did not clear the bacilli, as more than 1 log CFU remained, suggesting a possible antagonism between the two drugs, which was also reported when RIF was added to a TMC-PZA combination regimen (1, 21).”
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“…information about adaptive alleles provides an enormous potential for a broad range of disciplines including vaccine and drug development (e.g., Andries et al. 2005; Sequist et al. 2011), animal and plant breeding (e.g., Hufford et al. 2012; Daetwyler et al. 2014), pest management, biomedicine…”
BackgroundProspects for Advancing Tuberculosis Control Efforts through Novel Therapies
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“first new antimycobacterial to be approved by the US FDA for over 40 years [83, 84].”
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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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