Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis.

Int J Parasitol Drugs Drug Resist. 2018 12;8(3):440-450

Authors: Rufener R, Dick L, D'Ascoli L, Ritler D, Hizem A, Wells TNC, Hemphill A, Lundström-Stadelmann B

Abstract
The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti-theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 μM and 0.02 μM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity.

PMID: 30396011 [PubMed - indexed for MEDLINE]

Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro.

Int J Parasitol Drugs Drug Resist. 2018 12;8(3):379-385

Authors: Dilrukshi Herath HMP, Song H, Preston S, Jabbar A, Wang T, McGee SL, Hofmann A, Garcia-Bustos J, Chang BCH, Koehler AV, Liu Y, Ma Q, Zhang P, Zhao Q, Wang Q, Gasser RB

Abstract
Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads.

PMID: 30081296 [PubMed - indexed for MEDLINE]

In vitro antimicrobial activity of narasin against common clinical isolates associated with canine otitis externa.

Vet Dermatol. 2018 Apr;29(2):149-e57

Authors: Chan WY, Hickey EE, Khazandi M, Page SW, Trott DJ, Hill PB

Abstract
BACKGROUND: Antimicrobial resistance and antimicrobial stewardship are of ever-increasing importance in veterinary medicine. Re-purposing of old drugs that are not used in human medicine is one approach that addresses the emergence of multidrug resistance in canine skin and ear infections, and can reduce the use of critically important human antibiotic classes.
HYPOTHESIS/OBJECTIVES: To determine the antimicrobial activity of narasin, a polyether ionophore conventionally used as a rumen modifier and anticoccidial agent in production animals, against common clinical isolates of canine otitis externa (OE).
ANIMALS/ISOLATES: Clinical isolates (n = 110) from canine OE were tested, including 17 meticillin-susceptible Staphylococcus pseudintermedius (MSSP), 13 multidrug-resistant Staphylococcus pseudintermedius (MDRSP), and 20 each of β-haemolytic Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis and Malassezia pachydermatis.
METHODS: Bacterial and yeast isolates were subcultured, suspended in broth and inoculated into 96-well plates. Organisms were tested against concentrations of narasin ranging from 0.03 to 128 μg/mL. Minimal inhibitory concentrations (MICs) were determined after overnight incubation.
RESULTS: Narasin MICs for staphylococcal and streptococcal isolates ranged from 0.06 to 0.25 μg/mL; MIC50 and MIC90 values for both organisms were 0.125 μg/mL. No MICs were achieved for Pseudomonas or Proteus isolates. There was a weak antifungal effect against M. pachydermatis isolates (MIC 32 to >128 μg/mL).
CONCLUSIONS AND CLINICAL RELEVANCE: Narasin was effective against Gram-positive bacteria and had antifungal activity at higher concentrations against M. pachydermatis. However, the lack of Gram-negative activity would prevent its use as a sole antimicrobial agent in cases of canine OE.

PMID: 29363210 [PubMed - indexed for MEDLINE]

The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway.

Parasitol Res. 2019 Jan 29;:

Authors: da Silva Rodrigues JH, Miranda N, Volpato H, Ueda-Nakamura T, Nakamura CV

Abstract
Despite many efforts, the currently available treatments for leishmaniasis are not fully effective. To discover new medications, drug repurposing arises as a promising strategy. We present data that supports the use of the antidepressant clomipramine against Leishmania amazonensis. The drug presented selective activity at micromolar range against both the parasite forms and stimulated nitric oxide production in host macrophages. Regarding the mechanism of action, clomipramine led parasites do mitochondrial depolarization, which coupled with the inhibition of trypanothione reductase induced strong oxidative stress in the parasites. The effects observed in promastigotes included lipoperoxidation, plasma membrane permeabilization, and apoptosis hallmarks (i.e., DNA fragmentation, phosphatidylserine exposure, and cell shrinkage). The mechanism of action in both parasitic forms was quite similar, but amastigotes also exhibited energetic stress, reflected by a reduction of adenosine triphosphate levels. Such differential effects might be attributable to the metabolic particularities of each form of the parasitic. Ultrastructural alterations of the endomembrane system and autophagy were also observed, possibly indicating an adaptive response to oxidative stress. Our results suggest that clomipramine interferes with the redox metabolism of L. amazonensis. In spite of the cellular responses to recover the cellular homeostasis, parasites underwent programmed cell death.

PMID: 30694414 [PubMed - as supplied by publisher]

Ionophores as Potent Anti-malarials: A Miracle in the Making.

Curr Top Med Chem. 2019;18(23):2029-2041

Authors: Bharti H, Singal A, Raza M, Ghosh PC, Nag A

Abstract
Plasmodium has a complex life cycle that spans between mosquito and human. For survival and pathogenesis it banks upon dynamic alterations in ionic transport across organelle and plasma membrane. Being a fundamental contributor of crucial biological processes in parasite, ionic balance facilitates parasite invasion, augmentation and transmission. Past few decades have witnessed tremendous advancement in understanding the relevance of ionic transit in parasites. Perhaps, not surprisingly, disruption of ionic homeostasis was thought to be detrimental for parasite. Compounds like ionophores are known to facilitate ionic transport across membrane down their electrochemical gradient. Despite continuous effort, malaria treatment is still a challenge particularly due to the development of resistance among parasites against existing therapeutic options. However, repurposing the existing drugs can be advantageous over de novo drug development programs in terms of cost and associated risk factors. Ionophores, being used in coccidiosis have proven to be of significance in the treatment of experimental models of malaria. Several recent reports have highlighted the attractive potential of ionophores such as Monensin, Maduramicin, Valinomycin, etc., that can act against multiple stages of malarial parasite's life cycle. Improved variety of these molecules may help in mitigating the drug resistance problems as well. This review is an attempt to examine the relevant literature and provide insight into the mechanism and prospects of different classes of ionophores as promising anti-malarial potpourri.

PMID: 30499390 [PubMed - indexed for MEDLINE]

Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial.

J Antimicrob Chemother. 2019 Jan 25;:

Authors: Kumar A, Boradia VM, Thakare R, Singh AK, Gani Z, Das S, Patidar A, Dasgupta A, Chopra S, Raje M, Raje CI

Abstract
Background: The emergence of drug-resistant bacteria is a major hurdle for effective treatment of infections caused by Mycobacterium tuberculosis and ESKAPE pathogens. In comparison with conventional drug discovery, drug repurposing offers an effective yet rapid approach to identifying novel antibiotics.
Methods: Ethyl bromopyruvate was evaluated for its ability to inhibit M. tuberculosis and ESKAPE pathogens using growth inhibition assays. The selectivity index of ethyl bromopyruvate was determined, followed by time-kill kinetics against M. tuberculosis and Staphylococcus aureus. We first tested its ability to synergize with approved drugs and then tested its ability to decimate bacterial biofilm. Intracellular killing of M. tuberculosis was determined and in vivo potential was determined in a neutropenic murine model of S. aureus infection.
Results: We identified ethyl bromopyruvate as an equipotent broad-spectrum antibacterial agent targeting drug-susceptible and -resistant M. tuberculosis and ESKAPE pathogens. Ethyl bromopyruvate exhibited concentration-dependent bactericidal activity. In M. tuberculosis, ethyl bromopyruvate inhibited GAPDH with a concomitant reduction in ATP levels and transferrin-mediated iron uptake. Apart from GAPDH, this compound inhibited pyruvate kinase, isocitrate lyase and malate synthase to varying extents. Ethyl bromopyruvate did not negatively interact with any drug and significantly reduced biofilm at a 64-fold lower concentration than vancomycin. When tested in an S. aureus neutropenic thigh infection model, ethyl bromopyruvate exhibited efficacy equal to that of vancomycin in reducing bacterial counts in thigh, and at 1/25th of the dosage.
Conclusions: Ethyl bromopyruvate exhibits all the characteristics required to be positioned as a potential broad-spectrum antibacterial agent.

PMID: 30689890 [PubMed - as supplied by publisher]

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents.

Neural Regen Res. 2019 May;14(5):745-748

Authors: Mousa SA, Ayoub BM

Abstract
Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

PMID: 30688255 [PubMed]

Perspectives of Phage Therapy in Non-bacterial Infections.

Front Microbiol. 2018;9:3306

Authors: Górski A, Bollyky PL, Przybylski M, Borysowski J, Międzybrodzki R, Jończyk-Matysiak E, Weber-Dąbrowska B

Abstract
While the true value of phage therapy (PT) in human bacterial infections still awaits formal confirmation by clinical trials, new data have been accumulating indicating that in the future PT may be applied in the treatment of non-bacterial infections. Thus, "phage guests" may interact with eukaryotic cells and such interactions with cells of the immune system may protect human health (Guglielmi, 2017) and cause clinically useful immunomodulatory and anti-inflammatory effects when administered for therapeutic purposes (Górski et al., 2017; Van Belleghem et al., 2017). Recently, a vision of how these effects could translate into advances in novel means of therapy in a variety of human pathologies secondary to immune disturbances and allergy was presented (Górski et al., 2018a). In this article we present what is currently known about anti-microbial effects of phage which are not directly related to their antibacterial action and how these findings could be applied in the future in treatment of viral and fungal infections.

PMID: 30687285 [PubMed]

Trends and Characteristics of US Medicare Spending on Repository Corticotropin.

JAMA Intern Med. 2017 11 01;177(11):1680-1682

Authors: Hartung DM, Johnston K, Van Leuven S, Deodhar A, Cohen DM, Bourdette DN

PMID: 28892525 [PubMed - indexed for MEDLINE]

A Computational Framework for Genome-wide Characterization of the Human Disease Landscape.

Cell Syst. 2019 Jan 14;:

Authors: Lee YS, Krishnan A, Oughtred R, Rust J, Chang CS, Ryu J, Kristensen VN, Dolinski K, Theesfeld CL, Troyanskaya OG

Abstract
A key challenge for the diagnosis and treatment of complex human diseases is identifying their molecular basis. Here, we developed a unified computational framework, URSAHD (Unveiling RNA Sample Annotation for Human Diseases), that leverages machine learning and the hierarchy of anatomical relationships present among diseases to integrate thousands of clinical gene expression profiles and identify molecular characteristics specific to each of the hundreds of complex diseases. URSAHD can distinguish between closely related diseases more accurately than literature-validated genes or traditional differential-expression-based computational approaches and is applicable to any disease, including rare and understudied ones. We demonstrate the utility of URSAHD in classifying related nervous system cancers and experimentally verifying novel neuroblastoma-associated genes identified by URSAHD. We highlight the applications for potential targeted drug-repurposing and for quantitatively assessing the molecular response to clinical therapies. URSAHD is freely available for public use, including the use of underlying models, at ursahd.princeton.edu.

PMID: 30685436 [PubMed - as supplied by publisher]

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Peptidyl-prolyl isomerase-B is involved in Mycobacterium tuberculosis biofilm formation and a generic target for drug repurposing-based intervention.

NPJ Biofilms Microbiomes. 2019;5:3

Authors: Kumar A, Alam A, Grover S, Pandey S, Tripathi D, Kumari M, Rani M, Singh A, Akhter Y, Ehtesham NZ, Hasnain SE

Abstract
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), takes one human life every 15 s globally. Disease relapse occurs due to incomplete clearance of the pathogen and reactivation of the antibiotic tolerant bacilli. M.tb, like other bacterial pathogens, creates an ecosystem of biofilm formed by several proteins including the cyclophilins. We show that the M.tb cyclophilin peptidyl-prolyl isomerase (PpiB), an essential gene, is involved in biofilm formation and tolerance to anti-mycobacterial drugs. We predicted interaction between PpiB and US FDA approved drugs (cyclosporine-A and acarbose) by in-silico docking studies and this was confirmed by surface plasmon resonance (SPR) spectroscopy. While all these drugs inhibited growth of Mycobacterium smegmatis (M.smegmatis) when cultured in vitro, acarbose and cyclosporine-A showed bacteriostatic effect while gallium nanoparticle (GaNP) exhibited bactericidal effect. Cyclosporine-A and GaNP additionally disrupted M.tb H37Rv biofilm formation. Co-culturing M.tb in their presence resulted in significant (2-4 fold) decrease in dosage of anti-tubercular drugs- isoniazid and ethambutol. Comparison of the cyclosporine-A and acarbose binding sites in PpiB homologues of other biofilm forming infectious pathogens revealed that these have largely remained unaltered across bacterial species. Targeting bacterial biofilms could be a generic strategy for intervention against bacterial pathogens.

PMID: 30675370 [PubMed - in process]

Strategies against methicillin-resistant Staphylococcus aureus persisters.

Future Med Chem. 2018 04 01;10(7):779-794

Authors: Kim W, Hendricks GL, Tori K, Fuchs BB, Mylonakis E

Abstract
Chronic Staphylococcus aureus infections are complicated by frequent relapses not only from the development of drug resistance to conventional antibiotics, but also through the formation of persister bacterial cells. Bacterial persisters are in a transient, metabolically inactive state, making conventional antibiotics that target essential cellular growth processes ineffective, resulting in high clinical failure rates of antibiotic chemotherapy. The development of new antibiotics against persistent S. aureus is an urgent issue. Over the last decade, new strategies to identify S. aureus persister-active compounds have been proposed. This review summarizes the proposed targets, antipersister compounds and innovative methods that may augment conventional antibiotics against S. aureus persisters. The reviewed antipersister strategies can be summarized as two broad categories; directly targeting growth-independent targets and potentiating existing, ineffective antibiotics by aiding uptake or accessibility.

PMID: 29569952 [PubMed - indexed for MEDLINE]

The Ecstasy and Agony of Assay Interference Compounds.

J Med Chem. 2017 03 23;60(6):2165-2168

Authors: Aldrich C, Bertozzi C, Georg GI, Kiessling L, Lindsley C, Liotta D, Merz KM, Schepartz A, Wang S

PMID: 28244745 [PubMed - indexed for MEDLINE]

Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning.

Daru. 2019 Jan 23;:

Authors: Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H

Abstract
OBJECTIVES: Despite advances in our understanding of metabolic syndrome (MetS) and the treatment of each of its components separately, currently there is no single therapy approved to manage it as a single condition. Since multi-drug treatment increases drug interactions, decreases patient compliance and increases health costs, it is important to introduce single therapies that improve all of the MetS components.
EVIDENCE ACQUISITION: We conducted a PubMed, Scopus, Google Scholar, Web of Science, US FDA, utdo.ir and clinicaltrial.gov search, gathered the most relevant preclinical and clinical studies that have been published since 2010, and discussed the beneficial effects of dipeptidyl peptidase (DPP)-4 inhibitors to prevent and treat different constituent of the MetS as a single therapy. Furthermore, the pharmacology of DPP-4 inhibitors, focusing on pharmacodynamics, pharmacokinetics, drug interactions and their side effects are also reviewed.
RESULTS: DPP-4 inhibitors or gliptins are a new class of oral anti-diabetic drugs that seem safe drugs with no severe side effects, commonly GI disturbance, infection and inflammatory bowel disease. They increase mass and function of pancreatic β-cells, and insulin sensitivity in liver, muscle and adipose tissue. It has been noted that gliptin therapy decreases dyslipidemia. DPP-4 inhibitors increase fatty oxidation, and cholesterol efflux, and decrease hepatic triglyceride synthase and de novo lipogenesis. They delay gastric emptying time and lead to satiety. Besides, gliptin therapy has anti-inflammatory and anti-atherogenic impacts, and improves endothelial function and reduces vascular stiffness.
CONCLUSION: The gathered data prove the efficacy of DPP-4 inhibitors in managing MetS in some levels beyond anti-diabetic effects. This review could be a lead for designing new DPP-4 inhibitors with greatest effects on MetS in future. Introducing drugs with polypharmacologic effects could increase the patient's compliance and decrease the health cost that there is not in multi-drug therapy. Graphical abstract ᅟ.

PMID: 30674032 [PubMed - as supplied by publisher]

Zika Virus: Origins, Pathological Action, and Treatment Strategies.

Front Microbiol. 2018;9:3252

Authors: Gorshkov K, Shiryaev SA, Fertel S, Lin YW, Huang CT, Pinto A, Farhy C, Strongin AY, Zheng W, Terskikh AV

Abstract
The Zika virus (ZIKV) global epidemic prompted the World Health Organization to declare it a 2016 Public Health Emergency of International Concern. The overwhelming experience over the past several years teaches us that ZIKV and the associated neurological complications represent a long-term world-wide challenge to public health. Although the number of ZIKV cases in the Western Hemisphere has dropped since 2016, the need for basic research and anti-ZIKV drug development remains strong. Re-emerging viruses like ZIKV are an ever-present threat in the 21st century where fast transcontinental travel lends itself to viral epidemics. Here, we first present the origin story for ZIKV and review the rapid progress researchers have made toward understanding of the ZIKV pathology and in the design, re-purposing, and testing-particularly in vivo-drug candidates for ZIKV prophylaxis and therapy ZIKV. Quite remarkably, a short, but intensive, drug-repurposing effort has already resulted in several readily available FDA-approved drugs that are capable of effectively combating the virus in infected adult mouse models and, most importantly, in both preventing maternal-fetal transmission and severe microcephaly in newborns in pregnant mouse models.

PMID: 30666246 [PubMed]

Enzymatic chokepoints and synergistic drug targets in the sterol biosynthesis pathway of Naegleria fowleri.

PLoS Pathog. 2018 09;14(9):e1007245

Authors: Zhou W, Debnath A, Jennings G, Hahn HJ, Vanderloop BH, Chaudhuri M, Nes WD, Podust LM

Abstract
Naegleria fowleri is a free-living amoeba that can also act as an opportunistic pathogen causing severe brain infection, primary amebic meningoencephalitis (PAM), in humans. The high mortality rate of PAM (exceeding 97%) is attributed to (i) delayed diagnosis, (ii) lack of safe and effective anti-N. fowleri drugs, and (iii) difficulty of delivering drugs to the brain. Our work addresses identification of new molecular targets that may link anti-Naegleria drug discovery to the existing pharmacopeia of brain-penetrant drugs. Using inhibitors with known mechanism of action as molecular probes, we mapped the sterol biosynthesis pathway of N. fowleri by GC-MS analysis of metabolites. Based on this analysis, we chemically validated two enzymes downstream to CYP51, sterol C24-methyltransferase (SMT, ERG6) and sterol Δ8-Δ7 -isomerase (ERG2), as potential therapeutic drug targets in N. fowleri. The sterol biosynthetic cascade in N. fowleri displayed a mixture of canonical features peculiar to different domains of life: lower eukaryotes, plants and vertebrates. In addition to the cycloartenol→ergosterol biosynthetic route, a route leading to de novo cholesterol biosynthesis emerged. Isotopic labeling of the de novo-synthesized sterols by feeding N. gruberi trophozoites on the U13C-glucose-containing growth medium identified an exogenous origin of cholesterol, while 7-dehydrocholesterol (7DHC) had enriched 13C-content, suggesting a dual origin of this metabolite both from de novo biosynthesis and metabolism of scavenged cholesterol. Sterol homeostasis in Naegleria may be orchestrated over the course of its life-cycle by a "switch" between ergosterol and cholesterol biosynthesis. By demonstrating the growth inhibition and synergistic effects of the sterol biosynthesis inhibitors, we validated new, potentially druggable, molecular targets in N. fowleri. The similarity of the Naegleria sterol Δ8-Δ7 -isomerase to the human non-opioid σ1 receptor, implicated in human CNS conditions such as addiction, amnesia, pain and depression, provides an incentive to assess structurally diverse small-molecule brain-penetrant drugs targeting the human receptor for anti-Naegleria activity.

PMID: 30212566 [PubMed - indexed for MEDLINE]

Drug repurposing for Dravet syndrome in scn1Lab-/- mutant zebrafish.

Epilepsia. 2019 Jan 20;:

Authors: Sourbron J, Partoens M, Scheldeman C, Zhang Y, Lagae L, de Witte P

Abstract
Dravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset during the first year of life. Zebrafish models recapitulating human diseases are often used as drug discovery platforms, but also for drug repurposing testing. It was recently shown that pharmacological modulation of three serotonergic (5-HT) receptors (5-HT1D , 5-HT2C , 5-HT2A ) exerts antiseizure effects in a zebrafish scn1Lab-/- mutant model of DS. Using the zebrafish DS model, our aim was to examine the possibility of repurposing efavirenz (EFA), lisuride (LIS), and rizatriptan (RIZA), marketed medicines with a 5-HT on- or off-target profile, as antiepileptic drugs for DS. To examine whether these compounds have a broader antiseizure profile, they were tested in pentylenetetrazol and ethyl ketopentenoate (EKP) zebrafish models. Pharmacological effects were assessed by locomotor behavior, local field potential brain recordings, and bioluminescence. EFA was active in all models, whereas LIS was selectively active in the zebrafish DS model. Mainly, a poor response was observed to RIZA. Taken together, our preclinical results show that LIS could be a potential candidate for DS treatment. EFA was also active in the EKP model, characterized by a high level of treatment resistance, and hence these data are potentially important for future treatment of drug-resistant epilepsy.

PMID: 30663052 [PubMed - as supplied by publisher]

Repurposing Screen Identifies Unconventional Drugs With Activity Against Multidrug Resistant Acinetobacter baumannii.

Front Cell Infect Microbiol. 2018;8:438

Authors: Cheng YS, Sun W, Xu M, Shen M, Khraiwesh M, Sciotti RJ, Zheng W

Abstract
Antibiotic-resistant nosocomial infections are an emerging public health issue; carbapenem-resistant gram-negative bacteria such as Acinetobacter baumannii are among the pathogens against which new therapeutic agents are desperately needed. Drug repurposing has recently emerged as an alternative approach to rapidly identifying effective drugs and drug combinations to combat drug resistant bacteria. We performed a drug repurposing screen against a highly virulent, multidrug resistant, Acinetobacter baumannii strain AB5075. This strain, isolated from a patient, is resistant to 25 first-line antibiotics for gram-negative bacteria. A compound screen using a bacterial growth assay led to identification and confirmation of 43 active compounds. Among these confirmed compounds, seven are approved drugs or pharmacologically active compounds for non-antimicrobial indications. Three of these drugs, 5-fluorouracil, fluspirilene, and Bay 11-7082 resensitized strain AB5075 to azithromycin and colistin in a two-drug combination format. The approach using a drug repurposing screen with a pathogen sample isolated from a patient and a high throughput bacterial growth assay led to the successful identification of new drug combinations to overcome a multidrug resistant bacterial infection.

PMID: 30662875 [PubMed - in process]

Drug Repurposing for Retinoblastoma: Recent Advances.

Curr Top Med Chem. 2019 Jan 19;:

Authors: Dandu K, Kallamadi PR, Thakur SS, Rao CM

Abstract
Retinoblastoma is the intraocular malignancy that occurs during early childhood. The current standard of care includes chemotherapy followed by focal consolidative therapies, and enucleation. Unfortunately, these are associated with many side and late effects. New drugs and/or drug combinations need to be developed for safe and effective treatment. This compelling need stimulated efforts to explore drug repurposing for retinoblastoma. While conventional drug development is a lengthy and expensive process, drug repurposing is a faster, alternate approach, where an existing drug, not meant for treating cancer, can be repurposed to treat retinoblastoma. The present article reviews various attempts to test drugs approved for different purposes such as calcium channels blockers, non-steroidal anti-inflammatory drugs, cardenolides, antidiabetic, antibiotics and antimalarial for treating retinoblastoma. It also discusses other promising candidates that could be explored for repurposing for retinoblastoma.

PMID: 30659544 [PubMed - as supplied by publisher]