Desirable drug–drug interactions or when a matter of concern becomes a renewed therapeutic strategy

Guieu, Benjamin; Jourdan, Jean‐Pierre; Dreneau, Aurore; Willand, Nicolas; Rochais, Christophe; Dallemagne, Patrick

doi:10.1016/j.drudis.2020.11.026

Cited by 11 publications

(14 citation statements)

References 97 publications

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“…Lastly, BVL-GSK098 ( 35 ) is an amido-piperidine derivative that Bioversys AG has developed in collaboration with GSK, the Pasteur Institute Lille, and the University of Lille, France . Compound 35 boosts the bactericidal activity of two important Group C prodrugs that are used for the treatment of MDR-TB, ethionamide (ETH, 16 ) and prothionamide ( 17 ), and restores sensitivity toward bacterial strains that have become resistant to these drugs . While full details of the mechanism have yet to be disclosed, 35 appears to act on one of several transcriptional regulators in Mtb (VirS), stimulating the expression of an additional enzyme activator for ETH (MymA). , Based on the in vivo results, a reduction in the efficacious oral dosage of ETH by at least 3-fold is predicted in humans .…”

Section: Current Status Of New Tb Drugs In Clinical Developmentmentioning

confidence: 99%

“…Aside from direct inhibitors of InhA, there are also compounds that have an indirect but similar overall effect. Like INH, the Group C MDR-TB drug ETH ( 16 ) is a prodrug that, when activated by the enzyme EthA, forms a covalent adduct with NAD, which binds to InhA and inhibits its activity . As noted in section , phase I candidate BVL-GSK098 ( 35 ) boosts the activity of ETH and overcomes acquired ETH resistance by interacting with a specific transcriptional regulator in Mtb , triggering the expression of a second enzyme activator for ETH (MymA) .…”

Section: Preclinical Promisesmentioning

confidence: 99%

“…The University of Lille team recently reported a further example of this strategy, with the oxadiazole derivative BDM71339 ( 68 ) (Figure ) being identified as a potent EthR inhibitor and ETH booster. This compound was discovered through a combination of fragment-based drug design, in silico docking, and further optimization, starting from a cocrystal structure of fragment 67 (Figure ) and EthR, the transcriptional repressor of EthA. The EthR inhibitor 68 displayed an EC 50 of 0.072 μM and possessed sufficient solubility (30 μM) and mouse microsomal stability ( t 1/2 19 min) to evaluate its in vivo boosting capability in the acute Mtb infection BALB/c mouse model.…”

Section: Preclinical Promisesmentioning

confidence: 99%

“…131 While full details of the mechanism have yet to be disclosed, 35 appears to act on one of several transcriptional regulators in Mtb (VirS), stimulating the expression of an additional enzyme activator for ETH (MymA). 131,132 Based on the in vivo results, a reduction in the efficacious oral dosage of ETH by at least 3fold is predicted in humans. 131 A phase IIa EBA study of 35 and ETH in comparison to INH has been planned for 2022.…”

Section: Current Status Of New Tb Drugs In Clinicalmentioning

confidence: 99%

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Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

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Section: Current Status Of New Tb Drugs In Clinical Developmentmentioning

confidence: 99%

Section: Preclinical Promisesmentioning

confidence: 99%

Section: Preclinical Promisesmentioning

confidence: 99%

Section: Current Status Of New Tb Drugs In Clinicalmentioning

confidence: 99%

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Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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“…The occurrence of DDIs often triggers unexpected pharmacological effects ( 7 ). In a few cases, DDIs are beneficial and can be exploited as therapeutic strategies for improving efficiency, avoiding toxicity, or minimizing drug resistance, such as the combination of β-lactams and clavulanic acid ( 8 ). However, most DDIs are unpleasant and detrimental, which can make patients exposed to the risks of side effects and toxicity and even deteriorate their physical conditions ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

DDInter: an online drug–drug interaction database towards improving clinical decision-making and patient safety

Xiong

Yang

Wang

et al. 2021

Nucleic Acids Research

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Drug-drug interaction (DDI) can trigger many adverse effects in patients and has emerged as a threat to medicine and public health. Despite the continuous information accumulation of clinically significant DDIs, there are few open-access knowledge systems dedicated to the curation of DDI associations. To facilitate the clinicians to screen for dangerous drug combinations and improve health systems, we present DDInter, a curated DDI database with comprehensive data, practical medication guidance, intuitive function interface, and powerful visualization to the scientific community. Currently, DDInter contains about 0.24M DDI associations connecting 1833 approved drugs (1972 entities). Each drug is annotated with basic chemical and pharmacological information and its interaction network. For DDI associations, abundant and professional annotations are provided, including severity, mechanism description, strategies for managing potential side effects, alternative medications, etc. The drug entities and interaction entities are efficiently cross-linked. In addition to basic query and browsing, the prescription checking function is developed to facilitate clinicians to decide whether drugs combinations can be used safely. It can also be used for informatics-based DDI investigation and evaluation of other prediction frameworks. We hope that DDInter will prove useful in improving clinical decision-making and patient safety. DDInter is freely available, without registration, at http://ddinter.scbdd.com/.

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Tebipenem and Sulopenem: Dynamic Duo or Double Trouble?

Mangum,

Pogue,

Barber

2024

Curr Infect Dis Rep

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Purpose of Review Antimicrobial resistance is a growing threat to public health, leading to millions of antibiotic-resistant infections and thousands of deaths annually in the USA. One concerning issue is the rise of extended-spectrum beta-lactamase (ESBL)–producing Enterobacterales. Current treatments often involve intravenous carbapenems, leading to prolonged hospital stays and financial burdens. Recent Findings To address this, new oral penem agents, tebipenem and sulopenem, are being investigated. They are administered as prodrugs, enhancing bioavailability before becoming active in the gastrointestinal tract, potentially treating multidrug-resistant infections in outpatient settings. Despite promise in clinical trials, challenges exist, such as tebipenem’s renal excretion, requiring dose adjustments for kidney dysfunction. Additionally, sulopenem failed noninferiority margins in trials, and neither drug has established susceptibility testing standards. Summary Tebipenem and sulopenem offer potential oral solutions for antimicrobial resistance, especially in urinary tract infections, but further research is needed for optimal dosing and susceptibility testing.

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Desirable drug–drug interactions or when a matter of concern becomes a renewed therapeutic strategy

Cited by 11 publications

References 97 publications

Tuberculosis Drug Discovery: Challenges and New Horizons

Tuberculosis Drug Discovery: Challenges and New Horizons

DDInter: an online drug–drug interaction database towards improving clinical decision-making and patient safety

Tebipenem and Sulopenem: Dynamic Duo or Double Trouble?

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