Bedaquiline: Current status and future perspectives

Khoshnood, Saeed; Goudarzi, Mehdi; Taki, Elahe; Darbandi, Atieh; Kouhsari, Ebrahim; Heidary, Mohsen; Motahar, Moloudsadat; Moradi, Mostafa; Bazyar, Hadi

doi:10.1016/j.jgar.2021.02.017

Cited by 52 publications

(39 citation statements)

References 103 publications

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“…Furthermore, most of the available drugs are burdened by major adverse events that need to be taken into account, particularly in the case of prolonged therapy. Interestingly, studies around the world have shown controversies in the definition of bedaquiline and delamanid resistance [ 88 , 89 ]. Unfortunately, up to now, resistance to both of the drugs has been reported in vitro, but standardized drug susceptibility testing has not been developed and agreed upon.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, up to now, resistance to both of the drugs has been reported in vitro, but standardized drug susceptibility testing has not been developed and agreed upon. Known mechanisms of resistance to bedaquiline include mutations within the atpE , Rv0678 , and pepQ genes [ 88 ], whereas delamanid-resistant bacilli have mutations in one of the five genes in the F420-dependent bio-activation pathway [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

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Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

et al. 2021

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Multidrug-resistant (MDR) tuberculosis (TB) has been emerging at an alarming rate over the last few years. It has been estimated that about 3% of all pediatric TB is MDR, meaning about 30,000 cases each year. Although most children with MDR-TB can be successfully treated, up to five years ago effective treatment was associated with a high incidence of severe adverse effects and patients with extensively drug-resistant (XDR) TB had limited treatment options and no standard regimen. The main objective of this manuscript is to discuss our present knowledge of the management of MDR- and XDR-TB in children, focusing on the characteristics and available evidence on the use of two promising new drugs: bedaquiline and delamanid. PubMed was used to search for all of the studies published up to November 2020 using key words such as “bedaquiline” and “delamanid” and “children” and “multidrug-resistant tuberculosis” and “extensively drug-resistant tuberculosis”. The search was limited to articles published in English and providing evidence-based data. Although data on pediatric population are limited and more studies are needed to confirm the efficacy and safety of bedaquiline and delamanid, their use in children with MDR-TB/XDR-TB appears to have good tolerability and efficacy. However, more evidence on these new anti-TB drugs is needed to better guide their use in children in order to design effective shorter regimens and reduce adverse effects, drug interactions, and therapeutic failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

et al. 2021

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“…The antibiotic resistance pattern of the patients was severe (> 30% with XDR-TB). The median number of resistant drugs was 6 (Blair and Scott, 2015;Diel et al, 2015;Diel et al, 2015;Cox et al, 2018;World Health Organization, 2020;Khoshnood et al, 2021) and 5 (Blair and Scott, 2015;Cox et al, 2018;Heidary et al, 2019;Khoshnood et al, 2021) in patients with a final outcome and overall cohort, respectively. The proportion of patients achieving culture conversion and sputum smear ranged from 88.8 to 89.3% (patients with a final outcome) to 92.8% and 93.4% (whole cohort), respectively.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…Drug progress in TB therapeutics has evolved considerably with the introduction of two new drugs, namely, bedaquiline (BDQ) and delamanid (DLM). The European Medicines Agency conditionally approved DLM as a first-in-class bicyclic nitroimidazole, relying on promising results from phase IIb trial and with regard to medical need for treating MDR-TB (Blair and Scott, 2015;Khoshnood et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant Mycobacterium tuberculosis

et al. 2021

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Multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis (MTB) remain a primary global threat to the end of tuberculosis (TB) era. Delamanid (DLM) is a nitro-dihydro-imidazooxazole derivative utilized to treat MDR-TB. DLM has distinct mechanism of action, inhibiting methoxy- and keto-mycolic acid (MA) synthesis through the F420 coenzyme mycobacteria system and generating nitrous oxide. While DLM resistance among MTB strains is uncommon, there are increasing reports in Asia and Europe, and such resistance will prolong the treatment courses of patients infected with MDR-TB. In this review, we address the antimycobacterial properties of DLM, report the global prevalence of DLM resistance, discuss the synergism of DLM with other anti-TB drugs, and evaluate the documented clinical trials to provide new insights into the clinical use of this antibiotic.

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“…However, when compared the ethambutole and pretomanid's (a new drug approved for the treatment of multidrug-resistant TB [61]) FoR, the values registered for compounds 1, 18 and 22 were 10 times lower, while compared to isoniazid, the FoR was 100 fold reduced (10 −4 for isoniazid versus 10 −6 for tested compounds). Bedaquiline is the first drug from a new class, diarylquinolines, approved by FDA for the treatment of multidrug-resistant TB (MDR) [62], with a low FoR; compounds 1, 18 and 22 revealed similar low FoR values.…”

Section: Frequency Of Resistancementioning

confidence: 99%

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Казакова

Racoviceanu

Petrova

et al. 2021

IJMS

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Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.

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Bedaquiline: Current status and future perspectives

Cited by 52 publications

References 103 publications

Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant Mycobacterium tuberculosis

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

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