Niclosamide, a Drug with Many (Re)purposes

Kadri, Hachemi; Lambourne, Olivia A.; Mehellou, Youcef

doi:10.1002/cmdc.201800100

Cited by 89 publications

(68 citation statements)

References 49 publications

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“…Despite the promise of niclosamide as a PINK1 activator, it has a number of limitations that hinder its possible repurposing for the treatment of PD. First, niclosamide is a promiscuous compound that manipulates many signalling pathways in cells and in vivo . Deconvoluting the niclosamide‐mediated PINK1 activation mechanism from the other non‐PINK1‐related effects, albeit a challenge, would be extremely informative and would facilitate the discovery of more‐specific PINK1 activators.…”

Section: Small‐molecule Pink1 Activatorsmentioning

confidence: 99%

“…Keen to discover safe smallm olecules that could manipulate mitochondrial membrane potentiala nd thus activate PINK1, we focused our attention on niclosamide (Scheme 2), ac linicala gent that has been reported in numerous studies to uncouple mitochondrial membrane potential. [22] Niclosamidei sa na nthelminthic drug that has been used for decades to treat tapeworm infections [23] and it has an encouraging safety profile in vivo. [22b, 24] Treating parkin-overexpressing HeLa cells, which express PINK1 endogenously,w ith niclosamide led to potent activation Scheme1.Nucleobase, nucleoside and ProTide activators of PINK1.…”

Section: Indirectpink1 Activatorsmentioning

confidence: 99%

“…First, niclosamide is ap romiscuous compound that manipulates many signalling pathways in cells and in vivo. [23] Deconvoluting the niclosamide-mediated PINK1 activation mechanism from the other non-PINK1-related effects, albeit ac hallenge, would be extremelyi nformativea nd would facilitate the discovery of more-specific PINK1a ctivators. Second, asadrug molecule, niclosamide has poor drug-like properties that include poor solubility and inefficient absorption.…”

Section: Indirectpink1 Activatorsmentioning

confidence: 99%

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Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Lambourne

Mehellou

2018

ChemBioChem

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PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in the mid‐2000s, when PINK1 mutations were found to cause early onset Parkinson's disease (PD). As most of the PD‐related mutations occurred in the kinase domain and impaired PINK1′s catalytic activity, it was suggested that small molecules that activated PINK1 would maintain mitochondrial quality control and, as a result, have neuroprotective effects. Working on this hypothesis, a few small‐molecule PINK1 activators that offer critical insights and distinct approaches for activating PINK1 have been discovered. Herein, we briefly highlight the discovery of these small molecules and offer insight into the future development of small‐molecule PINK1 activators as potential treatments for PD.

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Section: Small‐molecule Pink1 Activatorsmentioning

confidence: 99%

Section: Indirectpink1 Activatorsmentioning

confidence: 99%

Section: Indirectpink1 Activatorsmentioning

confidence: 99%

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Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Lambourne

Mehellou

2018

ChemBioChem

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“…Recently, several studies have suggested the potential of repurposing niclosamide for other medical applications, e.g ., niclosamide appears to modulate metabolic disorders and neurological conditions, and has antiproliferative effects against various cancers (17). The diverse pharmacological activities of niclosamide are likely the result of oxidative phosphorylation uncoupling and the modulation of signaling pathways (18, 19). Niclosamide exhibits antiviral activity against SARS-COV (20, 21), and is an effective antibiotic against Gram-positive and acid-fast pathogens ( e.g.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

Copp

Pletzer

Brown³

et al. 2020

Preprint

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21One avenue to combat multidrug-resistant Gram-negative bacteria is the co-administration 22 of multiple drugs (combination therapy), which can be particularly promising if drugs 23 synergize. The identification of synergistic drug combinations, however, is challenging. 24 Detailed understanding of antibiotic mechanisms can address this issue by facilitating the 25 rational design of improved combination therapies. Here, using diverse biochemical and 26 genetic assays, we reveal the molecular mechanisms of niclosamide, a clinically-approved 27 salicylanilide compound, and demonstrate its potential for Gram-negative combination 28 therapies. We discovered that Gram-negative bacteria possess two innate resistance 29 mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated 30 by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was 31 compromised, niclosamide became a potent antibiotic, dissipating the proton motive force 32 (PMF), increasing oxidative stress and reducing ATP production to cause cell death. These 33 insights guided the identification of diverse compounds that synergized with salicylanilides 34 when co-administered (efflux inhibitors, membrane permeabilizers, and antibiotics that are 35 expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may 36 have broad utility in combination therapies. We validate these findings in vivo using a 37 murine abscess model, where we show that niclosamide synergizes with the membrane 38 permeabilizing antibiotic colistin against high-density infections of multidrug-resistant 39 Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase 40 activity is a potential route to adaptive niclosamide resistance but show that this causes 41 collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how 42 mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can 43 rationally guide the discovery, development and stewardship of novel combination 44 therapies. 45 46 Importance 47There is a critical need for more effective treatments to combat multidrug-resistant Gram-48 negative infections. Combination therapies are a promising strategy, especially when these 49 enable existing clinical drugs to be repurposed as antibiotics. We reveal the mechanisms 50 of action and basis of innate Gram-negative resistance for the anthelmintic drug 51 niclosamide, and subsequently exploit this information to demonstrate that niclosamide 52 and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug 53 efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in 54 vitro against a diverse range of recalcitrant Gram-negative clinical isolates, and in vivo in 55 a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to 56 niclosamide, but show that evolution of these enzymes for enhanced niclosamide resistance 57 confers a collateral s...

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“…These effects of NCL have been linked to the ability to induce apoptosis, and targeting the dysregulated signaling pathways including Wnt/β-catenin and STAT3. In addition to its classical anticancer properties, it is also found to suppress the p65 NF-κB, NFATc-1, and MAPKs signaling in inflammatory diseases (Ahn et al, 2017;Kadri, Lambourne, & Mehellou, 2018;Ren et al, 2010;Wu et al, 2014).…”

mentioning

confidence: 99%

Repurposing an old drug for new use: Niclosamide in psoriasis‐like skin inflammation

Thatikonda

Pooladanda

Godugu

2019

Journal Cellular Physiology

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Drug discovery is an onerous, extremely expensive, and time‐consuming process. Instead, drug repurposing is an attractive strategy for exploiting novel indications for a drug beyond its original use. The untapped potential of drug repurposing compensates the barriers associated with the drug discovery pipeline. Psoriasis is an autoimmune skin disease, where hyperproliferation of keratinocytes and exaggerated immune responses are the important hallmarks of the disease. Extensive in vitro and preclinical research has demonstrated that niclosamide was found to exert potent anticancer and anti‐inflammatory properties by targeting STAT3, p65 NF‐κB, and NFATc‐1 signaling paradigm with minimal host toxicity. From the disease perspective, the static intracellular molecular network in both cancer and psoriasis share overlapping pathological features in terms of hyperproliferation and chronic inflammation, which is mediated by the aforementioned signaling cascade. The plausible mechanistic relevance has prompted us to investigate the implementation of niclosamide for repositioning in psoriasis. Our in vitro and in vivo findings suggest that niclosamide inhibits keratinocytes hyperproliferation by reactive oxygen species‐mediated apoptosis through the loss of mitochondrial membrane potential, cell cycle arrest at Sub G1 phase, and DNA fragmentation. Furthermore, niclosamide treatment resulted in abrogation of lipopolysaccharide‐induced inflammatory cytokine levels in murine macrophages. Additionally, our results provided a preclinical rationale in imiquimod (IMQ)‐induced BALB/c mouse model, where niclosamide diligently mitigated the IMQ‐induced epidermal hyperplasia and inflammation by downregulating STAT3, p65 NF‐κB, and NFATc‐1 transcription factors along with Akt, Ki‐67, and ICAM‐1 protein expression.

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Niclosamide, a Drug with Many (Re)purposes

Cited by 89 publications

References 49 publications

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

Repurposing an old drug for new use: Niclosamide in psoriasis‐like skin inflammation

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