Repurposing disulfiram to target infections caused by non-tuberculous mycobacteria

Das, Swetarka; Garg, Tanu; Chopra, Sidharth; Dasgupta, Arunava

doi:10.1093/jac/dkz018

Cited by 42 publications

(27 citation statements)

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“…Drug repurposing (15,16) could be a strategy to identify a potential FDA-approved drug for the control of P. insidiosum. Disulfiram (originally approved to treat alcoholism) exhibits antimicrobial activity against various pathogens (18)(19)(20)(21)(22)(23). We explored whether disulfiram possesses The Repurposed Drug Disulfiram Inhibits P. insidiosum Antimicrobial Agents and Chemotherapy any anti-P. insidiosum effect.…”

Section: Discussionmentioning

confidence: 99%

“…Disulfiram is an FDA-approved drug used in the treatment of chronic alcoholism for decades (18). Several reports have shown that disulfiram markedly inhibits various pathogens, including Staphylococcus aureus (19), Pseudomonas aeruginosa (20), Giardia lamblia (21), Mycobacterium tuberculosis (22), and nontuberculous mycobacteria (23). The antimicrobial property of disulfiram could result from the inactivation of target enzymes, such as aldehyde dehydrogenase (ALDH), urease (URE), carbamate kinase (CK), and dopamine beta-hydroxylase (DBH) (21,(24)(25)(26).…”

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confidence: 99%

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The Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosum

Krajaejun

Lohnoo

Yingyong

et al. 2019

Antimicrob Agents Chemother

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Pythium insidiosum is an oomycete microorganism that causes a lifethreatening infectious disease, called pythiosis, in humans and animals. The disease has been increasingly reported worldwide. Conventional antifungal drugs are ineffective against P. insidiosum. Treatment of pythiosis requires the extensive removal of infected tissue (i.e., eye and leg), but inadequate surgery and recurrent infection often occur. A more effective treatment is needed for pythiosis patients. Drug repurposing is a promising strategy for the identification of a U.S. Food and Drug Administration-approved drug for the control of P. insidiosum. Disulfiram has been approved to treat alcoholism, but it exhibits antimicrobial activity against various pathogens. In this study, we explored whether disulfiram possesses an anti-P. insidiosum activity. A total of 27 P. insidiosum strains, isolated from various hosts and geographic areas, were susceptible to disulfiram in a dose-dependent manner. The MIC range of disulfiram against P. insidiosum (8 to 32 mg/liter) was in line with that of other pathogens. Proteogenomic analysis indicated that several potential targets of disulfiram (i.e., aldehyde dehydrogenase and urease) were present in P. insidiosum. By homology modeling and molecular docking, disulfiram can bind the putative aldehyde dehydrogenase and urease of P. insidiosum at low energies (i.e., -6.1 and -4.0 Kcal/mol, respectively). Disulfiram diminished the biochemical activities of these enzymes. In conclusion, disulfiram can inhibit the growth of many pathogenic microorganisms, including P. insidiosum. The drug can bind and inactivate multiple proteins of P. insidiosum, which may contribute to its broad antimicrobial property. Drug repurposing of disulfiram could be a new treatment option for pythiosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosum

Krajaejun

Lohnoo

Yingyong

et al. 2019

Antimicrob Agents Chemother

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“…The remaining 21 infected mice were divided randomly into three groups: group 1 (control administered PBS with 0.5% methylcellulose-0.1% Tween 80 by daily oral gavage for 2 weeks), group 2 (treated with 50 mg/kg AR-12 in PBS with 0.5% methylcellulose-0.1% Tween 80 administered by daily oral gavage for 2 weeks), and group 3 (administered 50 mg/kg amikacin intramuscularly for 2 weeks daily). The dosage of amikacin was selected based upon the report of Das et al (36). The same AR-12 dose was chosen to facilitate a comparison of antibacterial effects.…”

Section: Methodsmentioning

confidence: 99%

AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus

Zhang

Zou

Guo

et al. 2020

Antimicrob Agents Chemother

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Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo. Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular M. abscessus residing within macrophage was also evaluated. Finally, the potency of AR-12 in vivo was determined in a neutropenic mouse model that mimics pulmonary M. abscessus infection. AR-12 exhibited high anti-M. abscessus activity in vitro, with an MIC50 of 4 mg/liter (8.7 μM) and an MIC90 of 8 mg/liter (17.4 μM) for both subsp. abscessus and subsp. massiliense. AR-12 and amikacin exhibited comparable bactericidal activity against extracellular M. abscessus in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with M. abscessus. No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against M. abscessus in vitro and in vivo and does not antagonize the most frequently used anti-M. abscessus drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat M. abscessus infections.

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“…Also, the strategy of drug-repurposing offers an opportunity to overcome the threats associated with antimicrobial resistance (AMR) Kaul et al (2019). Some examples of re-positioned drugs include chlorocyclizine, an anti-allergic drug re-purposed as an antiviral He et al (2015), sertraline, an antidepressant drug as an antifungal Villanueva-Lozano et al (2018) and disulfiram, an anti-alcoholic drug repurposed as an antibacterial Das et al (2019); Thakare et al (2019).…”

Section: Introductionmentioning

confidence: 99%

Computational prediction of Drug-Disease association based on Graph-regularized one bit Matrix completion

Mongia

Chouzenoux

Majumdar

2020

Preprint

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MotivationInvestigation of existing drugs is an effective alternative to discovery of new drugs for treating diseases. This task of drug re-positioning can be assisted by various kinds of computational methods to predict the best indication for a drug given the open-source biological datasets. Owing to the fact that similar drugs tend to have common pathways and disease indications, the association matrix is assumed to be of low-rank structure. Hence, the problem of drug-disease association prediction can been modelled as a low-rank matrix-completion problem.ResultsIn this work, we propose a novel matrix completion framework which makes use of the sideinformation associated with drugs/diseases for the prediction of drug-disease indications modelled as neighborhood graph: Graph regularized 1-bit matrix compeltion (GR1BMC). The algorithm is specially designed for binary data and uses parallel proximal algorithm to solve the aforesaid minimization problem taking into account all the constraints including the neighborhood graph incorporation and restricting predicted scores within the specified range. The results of the proposed algorithm have been validated on two standard drug-disease association databases (Fdataset and Cdataset) by evaluating the AUC across the 10-fold cross validation splits. The usage of the method is also evaluated through a case study where top 5 indications are predicted for novel drugs and diseases, which then are verified with the CTD database. The results of these experiments demonstrate the practical usage and superiority of the proposed approach over the benchmark methods.Contactaanchalm@iiitd.ac.in

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Repurposing disulfiram to target infections caused by non-tuberculous mycobacteria

Cited by 42 publications

References 8 publications

The Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosum

The Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosum

AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus

Computational prediction of Drug-Disease association based on Graph-regularized one bit Matrix completion

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