Respiratory syncytial virus is a major cause of acute lower respiratory tract infection in young children, immunocompromised adults, and the elderly. Intervention with small-molecule antivirals specific for respiratory syncytial virus presents an important therapeutic opportunity, but no such compounds are approved today. Here we report the structure of JNJ-53718678 bound to respiratory syncytial virus fusion (F) protein in its prefusion conformation, and we show that the potent nanomolar activity of JNJ-53718678, as well as the preliminary structure–activity relationship and the pharmaceutical optimization strategy of the series, are consistent with the binding mode of JNJ-53718678 and other respiratory syncytial virus fusion inhibitors. Oral treatment of neonatal lambs with JNJ-53718678, or with an equally active close analog, efficiently inhibits established acute lower respiratory tract infection in the animals, even when treatment is delayed until external signs of respiratory syncytial virus illness have become visible. Together, these data suggest that JNJ-53718678 is a promising candidate for further development as a potential therapeutic in patients at risk to develop respiratory syncytial virus acute lower respiratory tract infection.

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.New antituberculosis (anti-TB) drugs that have the potential to shorten the current duration of therapy for both active and latent tuberculosis and to improve the efficacy of treatment regimens for multidrug-resistant (MDR) TB are urgently needed.R207910 (TMC207), a diarylquinoline, is a new compound that exhibits a new mode of action (inhibition of ATP synthase) against mycobacteria (1, 6). The compound is being assessed in a phase IIb trial for the treatment of active tuberculosis in patients with MDR-TB. In vitro, R207910 is active against sensitive and resistant strains of Mycobacterium tuberculosis (1, 2). In mice, it accelerates bacterial clearance when it is combined with regimens active against both sensitive and MDR Mycobacterium tuberculosis (1, 10), Mycobacterium leprae (4), and Mycobacterium ulcerans (5).In the established murine model of tuberculosis, monotherapy with R207910 is as active as the standard WHO regimen, which combines rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA); and when it was combined with RIF-INH-PZA (RHZ), INH-PZA, or RIF-PZA, the lungs of mice became culture negative after just 2 months of treatment (1).When R207910 is combined with PZA, R207910 acts synergistically in the murine model (3). In fact, after only 2 months of treatment, the combination of R207910 and PZA led to the complete eradication of the 7.2 log 10 CFU that was present in the lungs of mice at the onset of treatment. Such a level of efficacy needed 4 months of treatment with the triple-drug combination RIF-moxifloxacin-PZA (11).An ext...

The efficacy of ATP synthase inhibitor TMC207 was assessed in early and late Mycobacterium avium infections in mice. In contrast to what was earlier observed for M. tuberculosis, a bacteriostatic effect was obtained. In vitro, the minimal bactericidal concentration (MBC)/MIC ratio was very high. The MBC was more relevant for assessment of pharmacokinetic/pharmacodynamic relationships than the MIC.Mycobacterium avium is a pathogen that causes disseminated disease in immunocompromised individuals and pulmonary disease in immunocompetent adults (15) and is far less susceptible than Mycobacterium tuberculosis to most antimicrobial agents; treatment options are very limited (7, 10). The most efficacious drugs are clarithromycin (CLA), the azalide antibiotic azithromycin, and amikacin (AMK). They are generally part of a multidrug regimen including rifamycins and ethambutol (10) and need to be administered daily for up to 24 months (10). These regimens are expensive and poorly tolerated (2, 6). TMC207 (also known as R207910) is a diarylquinoline ATP synthase inhibitor with potent activity against M. tuberculosis (1, 3, 13). It has broad antimycobacterial activity, with MICs against several clinical isolates of M. avium ranging from 0.007 to 0.25 g/ml (1, 8).Female C57BL/6J mice aged 6 to 7 weeks (Janvier Breeding, France) were infected intraperitoneally with 0.5 ml of a bacterial suspension containing 2.3 ϫ 10 7 CFU of M. avium 101. In a first group of 20 animals (Table 1), treatment started the day after infection (early infection model) and included a negative control, a positive control (CLA), and two test groups (TMC207 or CLA plus TMC207). Mice were sacrificed after 1 month of treatment. A second group of 165 mice was kept untreated for 1 month (late infection model) and then was treated with CLA alone, AMK alone, TMC207 alone, CLA plus AMK, CLA plus TMC207, AMK plus TMC207, or CLA plus AMK plus TMC207 for 4 months ( Table 1). Five animals from each group were sacrificed at monthly intervals. All drugs were given five times weekly at the following doses: 25 mg/kg body weight TMC207 orally, 200 mg/kg CLA orally, and 150 mg/kg AMK subcutaneously. Treatment effects were assessed by CFU counts, determined by plating three serial 10-fold dilutions of homogenized spleen suspensions onto Löwenstein-Jensen plates. The Student t test with Bonferroni correction of the P value was used to analyze CFU counts. As four and seven groups were compared, P values were adjusted to 0.0083 and 0.0024, respectively.In the early infection model, untreated control mice had 6.53 Ϯ 0.56 log 10 CFU counts at day 0, increasing to 8.0 Ϯ 0.9 log 10 CFU 1 month later (P ϭ 0.02). Monotherapy with CLA and TMC207 decreased CFU counts by 1.99 and 2.56 log 10 compared to late controls (P ϭ 0.005 and P ϭ 0.002, respectively). The combination of TMC207 and CLA did not improve the activity of the individual compounds (P Ͼ 0.05) ( Table 2).

Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed.

The levels of TMC207 (R207910) that can be reached in mouse organs and the sputa of treated patients easily exceed the MIC of the compound and can therefore interfere with in vitro bacterial titrations. We studied the usefulness of protein-enriched media for the prevention of such drug carryover effects. The average MIC of Mycobacterium tuberculosis was determined on three different media: unsupplemented 7H11 agar (MIC ‫؍‬ 0.03 g/ml), 7H11 agar supplemented with 5% bovine serum albumin (BSA; MIC ‫؍‬ 1 g/ml), and LowensteinJensen medium (MIC ‫؍‬ 14.33 g/ml). In a second stage of the study, the maximal noninhibitory concentrations (MNICs) of TMC207 were determined by adding TMC207 to the bacterial inoculum rather than to the culture medium. These MNICs were 0.97 g/ml for 7H11 agar, 32.33 g/ml for 7H11 agar with 5% BSA, and 96.33 g/ml for Lowenstein-Jensen medium. Both protein-enriched media were able to prevent drug carryover effects, but the use of 7H11 medium supplemented with 5% BSA is preferred for practical reasons.The drug carryover phenomenon can be defined as the inhibition of bacterial growth in vitro which is not due to the inhibition of growth in vivo but, rather, to the presence of high inhibitor concentrations in the tested samples. Failure to recognize the contribution of drug carryover may result in overestimation of a drug's in vivo efficacy. Antibiotics combining high levels of tissue penetration (high volumes of distribution) with low MICs, such as the diarylquinoline TMC207, the nitrodihydro-imidazo-oxazole OPC-67683, the nitroimidazo-oxazine PA-824, and the pyrrole LL-3858 (8), are at risk of displaying the carryover phenomenon when sputum from treated patients or organs from treated animals are cultivated for the isolation of Mycobacterium tuberculosis.TMC207 (also known as R207910) is being assessed in a phase IIb, placebo-controlled, double-blind, randomized trial for the evaluation of its antibacterial activity in subjects with smear-positive pulmonary infection caused by multidrug-resistant M. tuberculosis. Patients are treated for either 2 or 6 months with TMC207 in combination with a background regimen recommended for use for the treatment of multidrugresistant M. tuberculosis infections (a combination of secondline drugs, such as kanamycin, pyrazinamide, ofloxacin, and ethionamide).Following repeated oral administration of TMC207 to the mouse, rat, and dog, the tissue trough levels in all species are high in the lung, spleen, lymph nodes, and thymus, with an average tissue concentration/plasma concentration ratio above 30 (1). Theoretically, concentrations of 10 to 15 g/ml or higher could be achieved in the sputum after several months of treatment with TMC207, and these concentrations exceed the MIC of TMC207 against M. tuberculosis by Ͼ100-fold.When TMC207 was assessed in vitro by equilibrium dialysis, TMC207 was found to be extensively bound to plasma proteins, resulting in a free fraction in the buffer compartment below the quantification limit of the liquid chromatographytandem mass...