A structural insight of bedaquiline for the cardiotoxicity and hepatotoxicity (original) (raw)
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In Silico Pharmacology, 2021
Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (− 5.636 kcal/ mol) and highest binding free energy (ΔG bind − 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor.
Bedaquiline - A Novel Promising Discovery in Multidrug-Resistant Tuberculosis
Journal of Pharmaceutical Research, 2013
After acquired immunodeficiency syndrome (AIDS), tuberculosis (TB) is the leading cause of death worldwide due to a single infectious agent. Recently, drug-resistant strains of mycobacterium tuberculosis reported more horrible version of tuberculosis. There is threatful increase in multidrug resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) all over the world, so better treatment options are needed to control the global MDR-TB and XDR-TB epidemic. Bedaquiline, a diarylquinoline has a unique mechanism of action i.e. causes inhibition of the proton pump activity of the ATP synthase in mycobacterium tuberculosis and targets the energy metabolism. It acts as a promising new agent in patients with MDR-TB came in market recently. Bedaquiline can be combined with antituberculosis and antiretroviral agents. The drug showed good oral absorption, long terminal half-life and is metabolized mainly by cytochrome 450P3A4. It is recently been approved by U.S. Food and Drug...
Asian Journal of Chemistry, 2018
As the first US FDA approved drug for treating pulmonary multi drug resistant tuberculosis (MDR-TB) in the last 40 years, bedaquiline (TMC207, Sirturo TM) stands out as cynosure in the circles of synthetic chemists exploring new therapeutics against tuberculosis. The remarkable efficacy of bedaquiline in treating tuberuculosis lies in its ability to target the energy metabolism that affects both replicating as well as dormant forms of M. tuberculosis (MTB). Despite its promising antitubercular profile, bedaquiline raises serious concern with its string of side effects and emergence of resistant strains, warrants a quest for better substitutes. In the present work, we employed in silico methods like homology modeling and virtual screening to zero in on molecules that exhibit high affinity at the binding site of bedaquiline.
TMC207 becomes bedaquiline, a new anti-TB drug
Future Microbiology, 2013
TB still represents a serious public health problem. The latest reports estimate an incidence of 8.7 million cases in 2011 and 1.4 million deaths. Drug resistance contributed an estimated 630,000 cases of multidrug-resistant TB, making control of the disease harder. Recent reports show cases of TB that were almost resistant to all available antibiotics. Therefore, there is an urgent need to develop new anti-TB drugs with the potential of reducing the current length of treatment. Bedaquiline, formerly TMC207, is a new diarylquinoline antibiotic with specific activity against Mycobacterium tuberculosis and several nontuberculous mycobacteria. It acts by inhibiting ATP synthase, interfering with the energy generation needed by the bacterial cell. Based on clinical evaluations for safety, tolerability and efficacy, bedaquiline has recently received accelerated approval for the treatment of pulmonary multidrug-resistant TB in adults. This article will review the main aspects related to t...
Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?
Therapeutic advances in chronic disease, 2015
Acquired drug resistance by Mycobacterium tuberculosis (MTB) may result in treatment failure and death. Bedaquiline was recently approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). This report examines the available data on this novel drug for the treatment of MDR-TB. PubMed searches, last updated 18 February 2015, using the terms bedaquiline, TMC 207 and R207910 identified pertinent English citations. Citation reference lists were reviewed to identify other relevant reports. Pertinent MDR-TB treatment reports on the US Food and Drug Administration, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and Cochrane websites were also evaluated. Bedaquiline is an adenosine triphosphate (ATP) synthase inhibitor specific for MTB and some nontuberculous mycobacteria. The early bactericidal activity (EBA) of bedaquiline is delayed until ATP stores are depleted but subsequently it is similar to the EBA of isoniazid and rifampin. Bedaquiline...
Bedaquiline: Current status and future perspectives
Journal of Global Antimicrobial Resistance, 2021
The development of drug-resistant tuberculosis (TB) is a major threat worldwide. Based on World Health Organization (WHO) reports, it is estimated that more than 500 000 new cases of drug-resistant TB occur annually. In addition, there are alarming reports of increasing multidrug-resistant TB (MDR-TB) and the emergence of extensively drug-resistant TB (XDR-TB) from different countries of the world. Therefore, new options for TB therapy are required. Bedaquiline (BDQ), a novel anti-TB drug, has significant minimum inhibitory concentrations (MICs) both against drug-susceptible and drug-resistant TB. Moreover, BDQ was recently approved for therapy of MDR-TB. The current narrative review summarises the available data on BDQ resistance, describes its antimicrobial properties, and provides new perspectives on clinical use of this novel anti-TB agent.
Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis
Journal of Pharmacology and Pharmacotherapeutics, 2014
Tuberculosis (TB) is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB) and extensive drug-resistant tuberculosis (XDR-TB). Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB and XDR-TB relies on the drugs, which are less potent, more toxic and more costly and have to be administered for the longer duration. No new drug had come in to market for last 40 years, but the emergence of MDR-TB and XDR-TB has spurred interest in the development of novel drugs. For the effective treatment outcome, there is a dire need of new drugs with a different mechanism of action that can tackle both drug sensitive as well as drug-resistant strains. Bedaquiline is one such new drug with unique mechanism of action. Food and Drug Administration has approved bedaquiline for MDR-TB in December 2012. This article reviews the available evidence of efficacy and safety of bedaquiline.
Bactericidal mode of action of bedaquiline
The Journal of antimicrobial chemotherapy, 2015
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. 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. 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 consisten...
2018
Bedaquiline (BDQ) is the new first-in-class anti-tuberculosis (TB) compound belonging to the class of diarylquinolone with activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (M. tuberculosis). This novel drug has the immense potential to shorten TB treatment duration and has been advocated for multi-drug resistant (MDR)-TB treatment. Therefore, BDQ resistance can be considered as a major public health problem and molecular investigation of the same is the utmost need of the hour. The target based concept of resistance to BDQ is caused by mutation in c-ring of adenosine tri phosphate (ATP) synthase, a critical enzyme in the synthesis of ATP in M. tuberculosis coded by atpE gene. BDQ inhibits the proton pump of mycobacterial ATP synthase. To understand the molecular basis of BDQ resistance using mutants (MTs) as the emergence of strains resistant to BDQ may pose a potential threat to the TB control program, we undertook a initiative to study seven in vitro m...
Bioengineering & Translational Medicine
Tuberculosis (TB) claims the lives of 1.3 million people each year, more than any other bacterial infection. Hence great interest was generated in health communities upon the recent introduction of the new diarylquinoline anti-TB drug, bedaquiline. Bedaquiline acts by binding to the c-subunit in the membrane-bound F O portion of the F 1 F O-adenosine triphosphate (ATP) synthase, the universal enzyme that produces the ATP needed by cells. However, the mechanism of killing by bedaquiline is not fully understood. Recent observations related to the bactericidal effects of bedaquiline, which show that it is a potent uncoupler of respiration-driven ATP synthesis in Mycobacterium smegmatis are summarized. These observations are then interpreted from the standpoint of Nath's two-ion theory of energy coupling in ATP synthesis (Nath, Biophys. Chem. 2017; 230:45-52). Especial importance is given to the interpretation of biochemical fluorescence quenching data, and the differences between the uncoupling induced by bedaquiline from that by the classical anionic uncouplers of oxidative phosphorylation are highlighted. Suggestions for new experiments that could lead to a better understanding of the uncoupling mechanism are made. A model of uncoupling action by the drug is presented, and the biochemical basis underlying uncoupling of ATP synthesis and lethality in mycobacteria is elucidated. The major biological implications arising from these novel insights are discussed. It is hoped that the analysis will lead to a more fundamental understanding of biological energy coupling, uncoupling and transduction, and to an integrated view for the design of novel antimicrobials by future research in the field. K E Y W O R D S bactericidal mode of action, bedaquiline, bedaquiline as an H + /K + exchanger, bioenergetics, central role of succinate translocation in the creation of Δψ, F 1 F O-ATP synthase, fluorescence quenching, H + /K + antiport, mycobacteria, Mycobacterium tuberculosis, Nath's torsional mechanism of energy transduction and ATP synthesis, Nath's two-ion theory of biological energy coupling, oxidative phosphorylation (OXPHOS), uncouplers