Bedaquiline – The first ATP synthase inhibitor against multi drug resistant tuberculosis

Lakshmanan, Mageshwaran; Xavier, Alphienes Stanley

doi:10.1016/j.jyp.2013.12.002

Cited by 71 publications

(42 citation statements)

References 24 publications

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“…In fact, the first drug approved to treat multidrug-resistant tuberculosis, bedaquiline (104), acts on the ATP synthase, which is a multisubunit biomotor (Fig. 4C) (105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116).…”

Section: Perspectivesmentioning

confidence: 99%

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Zhao

Chelikani

et al. 2016

J Virol

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The intracellular parasitic nature of viruses and the emergence of antiviral drug resistance necessitate the development of new potent antiviral drugs. Recently, a method for developing potent inhibitory drugs by targeting biological machines with high stoichiometry and a sequential-action mechanism was described. Inspired by this finding, we reviewed the development of antiviral drugs targeting viral DNA-packaging motors. Inhibiting multisubunit targets with sequential actions resembles breaking one bulb in a series of Christmas lights, which turns off the entire string. Indeed, studies on viral DNA packaging might lead to the development of new antiviral drugs. Recent elucidation of the mechanism of the viral double-stranded DNA (dsDNA)-packaging motor with sequential one-way revolving motion will promote the development of potent antiviral drugs with high specificity and efficiency. Traditionally, biomotors have been classified into two categories: linear and rotation motors. Recently discovered was a third type of biomotor, including the viral DNA-packaging motor, beside the bacterial DNA translocases, that uses a revolving mechanism without rotation. By analogy, rotation resembles the Earth's rotation on its own axis, while revolving resembles the Earth's revolving around the Sun (see animations at http://rnanano.osu.edu/movie.html). Herein, we review the structures of viral dsDNA-packaging motors, the stoichiometries of motor components, and the motion mechanisms of the motors. All viral dsDNA-packaging motors, including those of dsDNA/dsRNA bacteriophages, adenoviruses, poxviruses, herpesviruses, mimiviruses, megaviruses, pandoraviruses, and pithoviruses, contain a high-stoichiometry machine composed of multiple components that work cooperatively and sequentially. Thus, it is an ideal target for potent drug development based on the power function of the stoichiometries of target complexes that work sequentially. Viruses reproduce themselves in host cells. Their intracellular parasitic nature poses a great challenge to antiviral drug development. Nevertheless, significant progress in antiviral drug discovery, such as new treatments for HIV (1), hepatitis B virus (2), herpesvirus (3), and influenza virus (4), has been made. Even though different approaches to new drug development, such as improving drug target binding affinity (5) and finding new targets with novel pharmacological mechanisms (6), have been explored, new infectious pandemic viruses that greatly threaten human health still emerge sporadically. In addition, the emergence of drug resistance necessitates new drug development. Highly potent drugs with elevated specificity are needed for overcoming viral diseases.In viral reproduction, the key step of genome packaging is usually accomplished by a biomotor using ATP. Linear doublestranded DNA (dsDNA) or dsRNA viruses package their genomes into preformed procapsids. This group includes dsDNA/dsRNA bacteriophages (7), adenoviruses (8), poxviruses (9, 120), herpesviruses (10, 11), mimiviruses, megavir...

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Section: Perspectivesmentioning

confidence: 99%

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Zhao

Chelikani

et al. 2016

J Virol

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“…6,[15][16][17] The dose is 400 mg (four tablets of 100 mg) once daily for first two weeks and then 200 mg 3 times a week (with at least 48 hours between doses) withtotal dose of 600 mg per week. It should only be administered as part of a MDRTBregimen under dots.…”

Section: Present Statusmentioning

confidence: 99%

“…The total duration of treatment is 24 weeks. [7][8][9]16 the safety and efficacy of bedaquiline in children and adolescents <18 years of age have not been studied. 5,16 …”

Section: Present Statusmentioning

confidence: 99%

BEDAQUILINE: A long but much fruitful wait since seventies

Khadka

2015

Med. J. Shree Birendra Hosp.

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Tuberculosis (TB) is a major health problem in developing countries one of the leading cause of deaths due to infectious disease in the world. Drug treatment had being successful with anti-tubercular drugs available, but Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are serious forms of TB which have emerged as real concern. Bedaquiline (TMC-207 or R207910), is a new anti TB agent been approved as a part of drug regimen therapy in pulmonary MDR-TB. Bedaquiline acts on energy metabolism of the bacteria. It acts as a bactericidal drug. There are two important black box warnings for this drug, firstly prolongation of QT interval and secondly increased risk of death with bedaquiline as compared to placebo treatment. Fast track approval for bedaquiline was based on two phase 2 trials. The FDA has approved bedaquiline on Dec 2012, for the treatment of MDR-TB in adults (>18 years) as part of combination therapy under the fast track designation, priority review and orphan-product designation based on two Phase II trials. Careful use of this drug along with monitoring of the potential adverse effects and drug interactions becomes very important, as this new anti-tubercular drug has being approved after forty years, since last anti tubercular drug was approved.doi: http://dx.doi.org/10.3126/mjsbh.v13i1.13000

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“…Components highly important for cancer cell growth have been explored as drug targets for the treatment of multidrug resistant cancer[2, 3]. The first FDA-approved drug to treat multidrug-resistant tuberculosis, bedaquiline, follows a novel mechanism of inhibiting the bacterial ATP synthase of M. tuberculosis and other mycobacterial species[4]. Another approach is to use nano-drug carriers to enhance the binding efficiency of drugs to cancer cells[5-8].…”

Section: Introductionmentioning

confidence: 99%

Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

Vieweger

Zhao

et al. 2015

Expert Opinion on Drug Delivery

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Introduction Multidrug resistance and the appearance of incurable diseases inspire the quest for potent therapeutics. Areas Covered We review a new methodology in designing potent drugs by targeting multi-subunit homomeric biological motors, machines, or complexes with Z>1 and K=1, where Z is the stoichiometry of the target, and K is the number of drugged subunits required to block the function of the complex. The condition is similar to a series, electrical circuit of Christmas decorations; failure of one light bulb causes the entire lighting system to lose power. In most multisubunit, homomeric biological systems, a sequential coordination or cooperative action mechanism is utilized, thus K equals 1. Drug inhibition depends on the ratio of drugged to nondrugged complexes. When K=1, and Z>1, the inhibition effect follows a power law with respect to Z, leading to enhanced drug potency. The hypothesis that the potency of drug inhibition depends on the stoichiometry of the targeted biological complexes was recently quantified by Yang-Hui's Triangle (or binomial distribution), and proved using a highly sensitive in vitro phi29 viral DNA packaging system. Examples of targeting homomeric bio-complexes with high stoichiometry for potent drug discovery are discussed. Expert Opinion Biomotors with multiple subunits are widespread in viruses, bacteria, and cells, making this approach generally applicable in the development of inhibition drugs with high efficiency.

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Bedaquiline – The first ATP synthase inhibitor against multi drug resistant tuberculosis

Cited by 71 publications

References 24 publications

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

BEDAQUILINE: A long but much fruitful wait since seventies

Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

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