Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis.

BACKGROUND: This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. METHODS: Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months' bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. RESULTS: Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. CONCLUSION: Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk-benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876-A Less Toxic and More Potent Analogue of Bedaquiline.

Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.

Mycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic "Escape" Pathways That Prolong Bacterial Survival.

Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate that Mycobacterium tuberculosis takes several days to be killed upon treatment with lethal concentrations of antibiotics both in vitro and in vivo To investigate how metabolic remodeling can enable transient bacterial survival during exposure to bactericidal concentrations of compounds, M. tuberculosis strain H37Rv was exposed to twice the MIC of isoniazid, rifampin, moxifloxacin, mefloquine, or bedaquiline for 24 h, 48 h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using quantitative shotgun mass spectrometry. Numerous sets of de novo bacterial proteins were identified over the 6-day treatment. Network analysis and comparisons between the drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in the nonpathogenic Mycobacterium smegmatis extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in M. tuberculosis prevented the pathogen from escaping the fast killing in vitro and in macrophages, as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.

Identification and synthesis of novel inhibitors of mycobacterium ATP synthase.

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.

Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort.

BACKGROUND: Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline. METHODS: We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment. RESULTS: A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8-235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ≥60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment. CONCLUSIONS: The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.

Bactericidal mode of action of bedaquiline.

OBJECTIVES: It is not fully understood why inhibiting ATP synthesis in Mycobacterium species leads to death in non-replicating cells. We investigated the bactericidal mode of action of the anti-tubercular F1Fo-ATP synthase inhibitor bedaquiline (Sirturo™) in order to further understand the lethality of ATP synthase inhibition. METHODS: Mycobacterium smegmatis strains were used for all the experiments. Growth and survival during a bedaquiline challenge were performed in multiple media types. A time-course microarray was performed during initial bedaquiline challenge in minimal medium. Oxygen consumption and proton-motive force measurements were performed on whole cells and inverted membrane vesicles, respectively. RESULTS: A killing of 3 log10 cfu/mL was achieved 4-fold more quickly in minimal medium (a glycerol carbon source) versus rich medium (LB with Tween 80) during bedaquiline challenge. Assessing the accelerated killing condition, we identified a transcriptional remodelling of metabolism that was consistent with respiratory dysfunction but inconsistent with ATP depletion. In glycerol-energized cell suspensions, bedaquiline caused an immediate 2.3-fold increase in oxygen consumption. Bedaquiline collapsed the transmembrane pH gradient, but not the membrane potential, in a dose-dependent manner. Both these effects were dependent on binding to the F1Fo-ATP synthase. CONCLUSIONS: Challenge with bedaquiline results in an electroneutral uncoupling of respiration-driven ATP synthesis. This may be a determinant of the bactericidal effects of bedaquiline, while ATP depletion may be a determinant of its delayed onset of killing. We propose that bedaquiline binds to and perturbs the a-c subunit interface of the Fo, leading to futile proton cycling, which is known to be lethal to mycobacteria.

Quinoline and quinolones: promising scaffolds for future antimycobacterial agents.

Tuberculosis (TB) is still a major health concern worldwide. The increasing incidences of multi-drug-resistant tuberculosis (MDR-TB) necessitate the development of new anti-TB drugs acting via novel mode of action. The search of newer drugs for TB led to the identification of several quinoline-based antimycobacterial agents against both the drug-sensitive and MDR-TB. These agents have been designed by substituting quinoline scaffold with diverse chemical functionalities as well as by modifying quinoline/quinolone-based antibacterial drugs. Several of quinoline/quinolone derivatives displayed excellent antimycobacterial activity and were found free of cytotoxicity. This review highlights the critical aspects of design and structure-activity relationship of quinoline- and quinolone-based antimycobacterial agents.

In vivo evaluation of antibiotic activity against Mycobacterium abscessus.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

ATP Synthase Inhibitors as Anti-tubercular Agents: QSAR Studies in Novel Substituted Quinolines.

BACKGROUND: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis. As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR & XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines have been reported with their antitubercular and ATP synthase inhibitory activity. METHODS: To understand the role of physicochemical parameters like hydrophobicity, electronic and steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR) studies have been carried out using the computed parameters as independent variable and activity (-log IC50/MIC) as the dependent variable. RESULTS: The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters have high predictivity as also shown on external data set and the mean value of the computed 3D parameters of enantiomers may be used in QSAR analysis for racemic compounds. CONCLUSION: These results are also substantiated by pharmacophore modeling. The similar dependence of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as the main target for antitubercular activity and the QSAR models may be useful in the identification of novel antitubercular agents.

Effect of Natural Phenolics on Pharmacokinetic Modulation of Bedaquiline in Rat to Assess the Likelihood of Potential Food-Drug Interaction.

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 plant-based natural products, typically phenolics, on in vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3',5-dihydroxyflavone-7-O-ß-d-galacturonide-4'-O-ß-d-glucopyranoside), and 6-gingerol should not be coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.

Development and validation of an LC-MS/MS method for the simultaneous determination of bedaquiline and rifabutin in human plasma.

This article describes the simultaneous determination of bedaquiline fumarate (TMC-207) and rifabutin in human plasma by stable isotope dilution tandem mass spectrometry. The methodology was developed for an investigation of potential drug-drug interactions of the two anti-tuberculosis drugs when given together to healthy human volunteers. Use of the two drugs in combination to treat disease caused by Mycobacterium tuberculosis is contemplated as the bacterium becomes resistant to many currently available drugs.

In vitro culture conditions affecting minimal inhibitory concentration of bedaquiline against M. tuberculosis.

OBJECTIVES: In developing a standardized drug susceptibility test for bedaquiline, it is very important to know which parameters might impact its activity in vitro and result in false resistance of the bacterium to bedaquiline. We aimed to assess the impact of different in vitro conditions on the minimal inhibitory concentration (MIC) of bedaquiline against Mycobacterium tuberculosis H37Rv reference strain. METHODS: The MIC of M. tuberculosis H37Rv strain was determined under different conditions such as inoculum size, pH, temperatures, log and stationary phase cultures, protein concentration, Tween 80 concentration, and labware plastics. RESULTS: Increases in bedaquiline MIC were observed with variations in inoculum size for M. tuberculosis H37Rv on agar or in broth, in protein concentration and labware plastics on agar, and with variations in pH and Tween 80 concentrations in broth. CONCLUSIONS: In order to obtain reproducible MIC results, bedaquiline MIC should be assessed using polystyrene plates or tubes, at pH 7, with a Tween 80 concentration of 0.02%, without protein enrichment and with an inoculum size up to 10(7) colony-forming unit (CFU)/mL on 7H11 agar or with 10(5)CFU/mL in 7H9 broth.

Bedaquiline for the treatment of drug-resistant tuberculosis.

Bedaquiline is a much-needed novel drug which is highly effective against drug-resistant tuberculosis. While its clinical development has been laudably fast-tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted.

Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis.

Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial adenosine triphosphate (ATP) synthase and represents the first novel class of antituberculosis agents in more than 40 years. Bedaquiline is indicated for the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with at least three other antitubercular drugs when no other effective regimen is available. The recommended bedaquiline dosage is 400 mg orally once/day for 2 weeks followed by 200 mg orally 3 times/week for 22 weeks. Bedaquiline should be administered with food, which increases the bioavailability 2-fold. Bedaquiline is metabolized by cytochrome P450 isoenzyme 3A4 and is impacted by both inducers and inhibitors of this isoenzyme. Concentration-dependent bactericidal activity was observed in laboratory and murine studies. Accelerated approval was granted in the United States and European Union based on the results of two phase IIb clinical studies that used sputum culture clearance as a surrogate end point for clinical efficacy. These studies showed greater sputum culture clearance up to week 24 for the bedaquiline group compared with placebo. Common adverse events in clinical trials included nausea, arthralgia, and headache. Serious adverse events included elevated serum transaminase levels and rate-corrected QT-interval prolongation. Unexplained higher mortality was seen in patients receiving bedaquiline versus those receiving placebo. Bedaquiline is a novel agent with a unique mechanism of action and has the potential to meet a great need in patients with MDR TB who have no other treatment options. Due to safety concerns and limited clinical information, phase III trials are needed to fully determine its place in therapy.

Recent advances in tuberculosis: New drugs and treatment regimens.

The current treatment regimen against drug susceptible tuberculosis (DS-TB) was defined by the 1980s. Since then the emergence of the global HIV pandemic and the escalation of drug resistant (DR-) forms of TB have presented new challenges for therapeutic research. Priority goals include shortening DS-TB treatment, improving DR-TB treatment and making combined TB-HIV therapy easier. To help achieve these goals, a range of new drugs and treatment strategies are currently being evaluated. Phase IIb and III clinical trials are ongoing to assess combinations involving the high-dose rifamycins, the 8-methoxyquinolones, a diarylquinoline (bedaquiline) and the nitroimidazoles. Other compounds (e.g. novel oxazolidinones and ethylenediamines) are at earlier stages of clinical development. Overall, there are grounds for optimism that recent advances will contribute towards achievement of new treatment regimens in the foreseeable future. However, long-term investment, political commitment and scientific endeavour are crucial to ensure that progress is sustained and the benefits of recent advances reach those in the greatest need.

Bedaquiline for the treatment of pulmonary, multidrug-resistant tuberculosis in adults.

After AIDS, tuberculosis (TB) is the leading killer worldwide due to a single infectious agent. Recently, drug-resistant strains of Mycobacterium tuberculosis elicited even more severe versions of TB. Bedaquiline inhibits mycobacterial ATP synthase. It shows potent and selective activity in vitro against M. tuberculosis, and in vivo against murine models of TB. Bedaquiline can be combined with antituberculosis and antiretroviral agents. The product displays good oral absorption, has a long terminal half-life and is metabolized mainly by cytochrome P450 3A4. In a phase II clinical trial in patients with multidrug-resistant TB, bedaquiline (combined with the standard five-drug, second-line TB regimen), showed a time to 50% culture negative conversion of 78 days, with 81.0% and 52.4% efficacy at weeks 24 and 104, respectively. Bedaquiline was generally safe and well tolerated. At the end of 2012, the U.S. Food and Drug Administration approved bedaquiline (Sirturo®) as part of a combination therapy to treat adults with multidrug-resistant TB.

A Importância do Núcleo Quinolínico e seus Derivados no Desenvolvimento de Fármacos / Importance of quinoline nucleus and its derivatives in drug discovery

No campo da descoberta de fármacos, o núcleo quinolínico é uma importante classe de compostos heterocíclicos, visto que está presente em muitos produtos naturais e sintéticos, os quais possuem um amplo espectro de atividades biológicas. Portanto derivados quinolínicos têm sido explorados com muito êxito, principalmente, na descoberta de novos tuberculostáticos, o que pode ser exemplificado pelas promissoras perspectivas apresentadas pela substância TMC 207, atualmente em fase II de testes clínicos. Sendo assim, o objetivo deste artigo é analisar a importância do núcleo quinolínico no desenvolvimento de fármacos.