bedaquiline and Disease-Models--Animal

Topics: Animals; Antitubercular Agents; Biological Products; Biomarkers; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarylquinolines; Disease Models, Animal; Drug Combinations; Drug Design; Drug Evaluation, Preclinical; Humans; Quinolines

A new class of antibacterials, diarylquinolines, was identified. The lead compound, R207910 (TMC207), was able to inhibit Mycobacterium tuberculosis in vitro, in mice and in patients. R207910 targets the mycobacterial ATP synthase. In vitro, it displayed potent activities against both drug-sensitive and multidrug-resistant strains of M. tuberculosis. It was also strongly active against dormant bacilli in the Wayne's dormancy culture system, hypoxia and nitric oxide models. In the murine model, when used alone, it was as active as the triple combination of rifampicin+isoniazid+pyrazinamide. When added to the previous combination or substituted for isoniazid or rifampicin, the treatment including the combinations containing R207910 led to culture conversion after 2 months of therapy. When added to the combination used to treat MDR-TB or substituted for moxifloxacin or ethionamide, the combinations containing R207910 led to culture conversion after 2 months of therapy. In MDR-TB infected patients, R207910 combined with second line drugs was able to convert more sputum cultures (47.6%) than the placebo combined to second line drugs regimen (8.7%).

Topics: Animals; Anti-Infective Agents; Antitubercular Agents; Aza Compounds; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Ethionamide; Fluoroquinolones; Humans; Mice; Moxifloxacin; Mycobacterium tuberculosis; Placebos; Quinolines; Tuberculosis

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifabutin; Tuberculosis

TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.

Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Isoniazid; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Mitochondrial dysfunction during ischemic stroke ultimately manifests as ATP depletion. Mitochondrial ATP synthase upon loss of mitochondrial membrane potential during ischemia rapidly hydrolyses ATP and thus contributes to ATP depletion. Increasing evidence suggests that inhibition of ATP synthase limits ATP depletion and is protective against ischemic tissue damage. Bedaquiline (BDQ) is an anti-microbial agent, approved for clinical use, that inhibits ATP synthase of Mycobacteria; however recently it has been shown to act on mitochondrial ATP synthase, inhibiting both ATP synthesis and hydrolysis in low micromolar concentrations. In this study, we investigated whether preconditioning with BDQ can alleviate ischemia/reperfusion-induced brain injury in Wistar rats after middle cerebral artery occlusion-reperfusion and whether it affects mitochondrial functions. We found that BDQ was effective in limiting necrosis and neurological dysfunction during ischemia-reperfusion. BDQ also caused inhibition of ATPase activity, mild uncoupling of respiration, and stimulated mitochondrial respiration both in healthy and ischemic mitochondria. Mitochondrial calcium retention capacity was unaffected by BDQ preconditioning. We concluded that BDQ has neuroprotective properties associated with its action on mitochondrial respiration and ATPase activity.

Topics: Adenosine Triphosphate; Animals; Cell Respiration; Diarylquinolines; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Mitochondria; Mitochondrial Proton-Translocating ATPases; Neuroprotection; Neuroprotective Agents; Rats; Reperfusion Injury; Stroke

The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.. We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.. Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.. The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Linezolid; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Recurrence; Tuberculosis

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Lung disease caused by

Topics: Animals; Anti-Bacterial Agents; Diarylquinolines; Disease Models, Animal; Female; Humans; Mice, SCID; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

Topics: Animals; Antitubercular Agents; Buruli Ulcer; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Piperidines; Pyridines; Rifampin; Tetrazoles

Non-replicating persistent Mycobacterium tuberculosis is difficult to kill since the organisms become undetectable using our conventional diagnostic methods and tolerant to anti-TB drugs. Resuscitation-promoting factors (RPFs) have been used to 'wake up' non-replicating persisters, making them easy to detect. Bedaquiline is a novel bactericidal and sterilizing anti-TB drug with the potential to eradicate RPF-dependent persistent M. tuberculosis. We present the first head-to-head comparison between the standard anti-TB regimen and a bedaquiline-modified regimen in eradicating RPF-dependent persistent M. tuberculosis, using the well-defined Cornell Model.. M. tuberculosis-infected mice were treated for 14 weeks with either the standard regimen (rifampicin, isoniazid, pyrazinamide and ethambutol) or the same regimen where ethambutol was replaced by bedaquiline. The efficacy of both drug regimens was measured by cfu count elimination and eradication of persistent bacteria, which was evaluated using culture filtrate (CF) containing RPFs. At the end of treatment, the remaining cfu count-negative mice were administered hydrocortisone for 8 weeks. The induced disease relapse rates were determined by the percentage of mice that became positive for M. tuberculosis in the lung, spleen or both.. The bedaquiline-containing regimen achieved total organ cfu count clearance at 8 weeks after treatment initiation, faster than the standard regimen (14 weeks). Importantly, the bedaquiline-containing regimen removed CF-dependent persistent bacilli at 8 weeks, leading to no disease relapse.. A bedaquiline regimen eradicated persistent TB infections and completely prevented disease relapse in mice. These findings offer the potential for a faster cure for TB, with reduced relapse rate.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Mice; Mycobacterium tuberculosis; Recurrence; Treatment Outcome; Tuberculosis

Topics: Administration, Intravenous; Animals; Autoradiography; Diarylquinolines; Disease Models, Animal; Female; Humans; Lung; Mice; Positron-Emission Tomography; Tuberculosis; Whole Body Imaging

As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.

Topics: Adamantane; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Combinations; Ethylenediamines; Humans; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis

New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Pyrazinamide; Tuberculosis, Pulmonary

New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination of BDQ+PMD plus the oxazolidinone sutezolid (SZD) had sterilizing activity superior to that of the first-line regimen in a murine model of TB. The present experiments compared the activity of different oxazolidinones in combination with BDQ+PMD with or without PZA in the same model. The 3-drug regimen of BDQ+PMD plus linezolid (LZD) had sterilizing activity approaching that of BDQ+PMD+SZD and superior to that of the first-line regimen. The addition of PZA further enhanced activity. Reducing the duration of LZD to 1 month did not significantly affect the activity of the regimen. Halving the LZD dose or replacing LZD with RWJ-416457 modestly reduced activity over the first month but not after 2 months. AZD5847 and tedizolid also increased the bactericidal activity of BDQ+PMD, but they were less effective than the other oxazolidinones. These results provide optimism for safe, short-course oral regimens for drug-resistant TB that may also be superior to the current first-line regimen for drug-susceptible TB.

Topics: Animals; Antitubercular Agents; Bacterial Load; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Linezolid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Organophosphates; Oxazoles; Oxazolidinones; Pyrazinamide; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Bedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected against the development of resistant mutants in vivo. The adjunctive use of verapamil may permit use of lower doses of bedaquiline to be used and thereby reduce its dose-related toxicities in tuberculosis patients.

Topics: Animals; Antitubercular Agents; Calcium Channel Blockers; Diarylquinolines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Verapamil

New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.

Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazines; Oxazoles; Pyrazinamide; Random Allocation; Tuberculosis

Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen. Serial (125)I-DPA-713 SPECT imaging was compared with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and standard microbiology. Ex vivo studies were performed to characterize and correlate DPA-713 imaging with cellular and cytokine responses. Pulmonary (125)I-DPA-713 SPECT, but not (18)F-FDG PET, was able to correctly identify the bactericidal activities of the two tuberculosis treatments as early as 4 weeks after the start of treatment (P < 0.03). DPA-713 readily penetrated the fibrotic rims of necrotic and cavitary lesions. A time-dependent decrease in both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels was observed with treatments, with (125)I-DPA-713 SPECT correlating best with tissue TNF-α levels (ρ = 0.94; P < 0.01). (124)I-DPA-713 was also evaluated as a PET probe and demonstrated a 4.0-fold-higher signal intensity in the infected tuberculous lesions than uninfected controls (P = 0.03). These studies provide proof of concept for application of a novel noninvasive imaging biomarker to monitor tuberculosis treatments, with the potential for application for humans.

Topics: Acetamides; Animals; Antitubercular Agents; Cytokines; Diagnostic Imaging; Diarylquinolines; Disease Models, Animal; Female; Fluorodeoxyglucose F18; Iodine Radioisotopes; Lung; Mice, Inbred C3H; Mycobacterium tuberculosis; Positron-Emission Tomography; Pyrazoles; Pyrimidines; Tomography, Emission-Computed, Single-Photon; Tuberculosis

The prognosis of Mycobacterium abscessus infections is poor due to the lack of effective drug treatment. The objective of this study was to set up an animal model suitable to test antibiotic activity against M. abscessus.. The following mouse strains were evaluated: Swiss, BALB/c, C57BL/6, nude, beige, A/J, and GKO. Antibiotic activity was tested for clarithromycin, amikacin, cefoxitin, tigecycline, and bedaquiline (TMC207). Finally, we evaluated the 3-drug combination clarithromycin, cefoxitin, and amikacin.. Nude and GKO mice fulfilled criteria for the model but only nude mice offered sufficient availability for large therapeutic experiments. Among the 3 drugs usually combined for treatment of M. abscessus infection, cefoxitin was the most active because it improved survival and reduced bacillary loads in spleen whereas clarithromycin and amikacin prevented death but had little impact on bacillary loads. The triple-drug combination was not more active than cefoxitin alone. Tigecycline displayed bactericidal activity whereas bedaquiline was almost inactive.. Nude mice are an adequate model for in vivo chemotherapy studies. Among tested drugs, cefoxitin and tigecycline showed promising in vivo activity against M. abscessus. The best drug combination remains to be determined.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Female; Kidney; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Microbial Sensitivity Tests; Minocycline; Mycobacterium; Mycobacterium Infections; Spleen; Statistics, Nonparametric; Tigecycline

TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative, N-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro, TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of tuberculosis (TB) infection following oral administration of different doses of TMC207 or N-desmethyl TMC207 at 5 days per week for 4 weeks starting the day after intravenous infection with M. tuberculosis and following administration of different doses of TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after infection. Upon administration of N-desmethyl TMC207, maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC(168h)), and minimum plasma concentration (C(min)) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (E(max)) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log(10) reduction of the bacillary load at an average exposure (average concentration [C(avg)] or AUC(168h) divided by 168) of 2.7 μg/ml. Upon administration of the highest dose of TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log(10). TMC207 was estimated to contribute to a 1.8-log(10) reduction and its corresponding exposure (C(avg)) was 0.5 μg/ml. Optimal bactericidal activity with N-desmethyl TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with TMC207. Following administration of TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC(168h)) to TMC207 and N-desmethyl TMC207 mirrored this dose response, indicating that the bactericidal activity of TMC207 is concentration dependent a

Topics: Animals; Antitubercular Agents; Area Under Curve; ATP Synthetase Complexes; Bacterial Proteins; Biotransformation; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Drug Dosage Calculations; Female; Half-Life; Humans; Lung; Male; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinolines; Tuberculosis, Pulmonary

Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.

Topics: Acetamides; Amino Acid Sequence; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Discovery; Drugs, Investigational; Female; Genetic Engineering; Latent Tuberculosis; Linezolid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Oxazines; Oxazolidinones; Quinolines; Rifampin; Streptomycin; Structure-Activity Relationship; Xanthenes

The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model.. Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model).. Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment.. The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207, moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide.. In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18-24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.

Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Lung; Mice; Mycobacterium tuberculosis; Organ Size; Quinolines; Recurrence; Spleen; Sterilization; Survival Analysis; Tuberculosis

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.. The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.. Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid.. Outcomes included monthly lung colony-forming unit counts and relapse rates.. Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.. TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Latent Tuberculosis; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Quinolines; Rifampin; Stem Cells; Treatment Outcome

To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Quinolines; Secondary Prevention; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

TMC207, rifapentine, and moxifloxacin are in clinical testing for the treatment of tuberculosis. Five experimental regimens with various combinations of TMC207, rifapentine, moxifloxacin, and pyrazinamide were tested for their bactericidal and sterilizing potencies in Swiss mice intravenously inoculated with Mycobacterium tuberculosis bacilli. TMC207 had the strongest bactericidal efficacy, while rifapentine was the strongest contributor to sterilizing efficacy. The rank order of sterilizing potencies was different from the rank order of bactericidal potencies, underlining the importance of prioritizing new regimens designed to shorten the treatment duration by their sterilizing potencies rather than by their bactericidal potencies. Both 3 months of treatment with a regimen combining TMC207, pyrazinamide, and rifapentine and 5 months of treatment with a regimen combining TMC207, pyrazinamide, and moxifloxacin resulted in relapse rates similar to the rate obtained by 6 months of treatment with rifampin-isoniazid-pyrazinamide.

Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.. To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide).. The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.. Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week.. The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Lung; Mice; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

The diarylquinoline R207910 (TMC207) has potent bactericidal activity in a murine model of tuberculosis (TB), but its sterilizing activity has not been determined.. To evaluate the sterilizing activity of R207910-containing combinations in the murine model of TB.. Swiss mice were intravenously inoculated with 6 log(10) of Mycobacterium tuberculosis strain H37Rv, treated with R207910-containing regimens, and followed for 3 months to determine relapse rates (modified Cornell model).. Quantitative lung and spleen colony-forming unit counts and bacteriological relapse rates 3 months after the end of therapy were compared for the following regimens: 2, 3, or 4 months of R207910 (J) and pyrazinamide (Z) combined with rifampin (R) or isoniazid (H) or both and 3 or 4 months of a moxifloxacin (M)-containing regimen and 6 months of the standard WHO regimen RHZ. All J-treated mice were culture negative after 4 months of therapy. The relapse rate in the group treated with 4 months of JHRZ was similar to that of mice treated for 6 months with the RHZ regimen (6 vs. 17%; P = 0.54) and lower than that of RMZ (6 vs. 42%; P = 0,03), a moxifloxacin-containing regimen that was the most active in mice on once-daily basis.. Four months of treatment with some J-containing regimens was as effective as the 6-month standard regimen and more effective than 4 months of treatment with M-containing regimens. Supplementation of standard regimen (RHZ) with J or substitution of J for H may shorten the treatment duration needed to cure TB in patients.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Hydrolases; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Splenic

New drugs are needed to shorten the duration of tuberculosis treatment. R207910, a diarylquinoline, is very active against Mycobacterium tuberculosis both in vitro and in mice. In healthy volunteers, the coadministration of R207910 and rifampin induced the increased metabolism of R207910, resulting in a 50% reduction in the level of R207910 exposure. We assessed the impact of reducing the dose of R207910 on its efficacy when R207910 was combined with a background regimen of isoniazid, rifampin, and pyrazinamide. Addition of 25 mg/kg of body weight or 12.5 mg/kg R207910 to the background regimen resulted in faster bacterial clearance and culture negativity. The difference in efficacy between the two doses was not statistically significant. The minimal bactericidal dose of R207910 when it was tested as part of the combination was identical to that when it was tested as monotherapy. Because of the drug-drug interaction in humans, the activity of R207910 in humans could be less than that expected from studies with mice. Our data from the mouse model demonstrate that R207910 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of isoniazid, rifampin, and pyrazinamide. In killing kinetic studies, the bactericidal effect of R207910 in mice was modest during the first week of treatment, but it increased in the following 3 weeks, while the bactericidal activity of isoniazid was limited to the first week of treatment.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Interactions; Female; Humans; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Spleen; Tuberculosis, Pulmonary