Drug repositioning based on triangularly balanced structure for tissue-specific diseases in incomplete interactome.

Artif Intell Med. 2017 Mar;77:53-63

Authors: Yu L, Zhao J, Gao L

Abstract
Finding new uses for existing drugs has become a new strategy for decades to treat more patients. Few traditional approaches consider the tissue specificities of diseases. Moreover, disease genes, drug targets and protein interaction (PPI) networks remain largely incomplete and the relationships between drugs and diseases conform to the triangularly balanced structure. Therefore, based on tissue specificities of diseases, we apply the triangularly balanced theory and the module distance defined for incomplete interaction networks to build drug-disease associations. Our method is named as TTMD (Tissue specificity, Triangle balance theory and Module Distance). Firstly, we combine three different drug similarity networks. Then, in the tissue-specific PPI network of a disease, we calculate its similarities with drugs using module distance. Finally, breast cancer and hepatocellular carcinoma (HCC) are taken as case studies. In the top-5% of predicted associations, 96.9% and 90.3% results match with known associations in Comparative Toxicogenomics Database (CTD) for breast cancer and hepatocellular carcinoma respectively. Clinical verification, literature mining and KEGG pathways enrichment analysis are further conducted for the top-5% newly predicted associations. Overall, TTMD is an effective approach for predicting new drug indications for tissue-specific diseases and provides potential values for the treatments of complex diseases.

PMID: 28545612 [PubMed - in process]

AlzhCPI: A knowledge base for predicting chemical-protein interactions towards Alzheimer's disease.

PLoS One. 2017;12(5):e0178347

Authors: Fang J, Wang L, Li Y, Lian W, Pang X, Wang H, Yuan D, Wang Q, Liu AL, Du GH

Abstract
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD. Another 104 binary classifiers were further constructed to predict the CPI for 26 preclinical AD targets based on the naive Bayesian (NB) and recursive partitioning (RP) algorithms. The internal 5-fold cross-validation and external test set validation were applied to evaluate the performance of the training sets and test set, respectively. The area under the receiver operating characteristic curve (ROC) for the test sets ranged from 0.629 to 1.0, with an average of 0.903. In addition, we developed a web server named AlzhCPI to integrate the comprehensive information of approximately 204 binary classifiers, which has potential applications in network pharmacology and drug repositioning. AlzhCPI is available online at http://rcidm.org/AlzhCPI/index.html. To illustrate the applicability of AlzhCPI, the developed system was employed for the systems pharmacology-based investigation of shichangpu against AD to enhance the understanding of the mechanisms of action of shichangpu from a holistic perspective.

PMID: 28542505 [PubMed - in process]

Drug target prediction by multi-view low rank embedding.

IEEE/ACM Trans Comput Biol Bioinform. 2017 May 18;:

Authors: Li L, Cai M

Abstract
Drug repositioning has been a key problem in drug development, and heterogeneous data sources are used to predict drug-target interactions by different approaches. However, most of studies focus on a single representation of drugs or proteins. It has been shown that integrating multi-view representations of drugs and proteins can strengthen the prediction ability. For example, a drug can be represented by its chemical structure, or by its chemical response in different cells. A protein can be represented by its sequence, or by its gene expression values in different cells. The docking of drugs and proteins based on their structure can be considered as one view (structural view), and the chemical performance of them based on gene expression and drug response can be considered as another view (chemical view). In this work, we first propose a single-view approach of SLRE based on low rank embedding for an arbitrary view, and then extend it to a multi-view approach of MLRE, which could integrate both views. Our experiments show that our methods perform significantly better than baseline methods including single-view methods and multi-view methods. We finally report predicted drug target interactions for 30 FDA-approved drugs.

PMID: 28541222 [PubMed - as supplied by publisher]

Network mirroring for drug repositioning.

BMC Med Inform Decis Mak. 2017 May 18;17(Suppl 1):55

Authors: Park S, Lee DG, Shin H

Abstract
BACKGROUND: Although drug discoveries can provide meaningful insights and significant enhancements in pharmaceutical field, the longevity and cost that it takes can be extensive where the success rate is low. In order to circumvent the problem, there has been increased interest in 'Drug Repositioning' where one searches for already approved drugs that have high potential of efficacy when applied to other diseases. To increase the success rate for drug repositioning, one considers stepwise screening and experiments based on biological reactions. Given the amount of drugs and diseases, however, the one-by-one procedure may be time consuming and expensive.
METHODS: In this study, we propose a machine learning based approach for efficiently selecting candidate diseases and drugs. We assume that if two diseases are similar, then a drug for one disease can be effective against the other disease too. For the procedure, we first construct two disease networks; one with disease-protein association and the other with disease-drug information. If two networks are dissimilar, in a sense that the edge distribution of a disease node differ, it indicates high potential for repositioning new candidate drugs for that disease. The Kullback-Leibler divergence is employed to measure difference of connections in two constructed disease networks. Lastly, we perform repositioning of drugs to the top 20% ranked diseases.
RESULTS: The results showed that F-measure of the proposed method was 0.75, outperforming 0.5 of greedy searching for the entire diseases. For the utility of the proposed method, it was applied to dementia and verified 75% accuracy for repositioned drugs assuming that there are not any known drugs to be used for dementia.
CONCLUSION: This research has novelty in that it discovers drugs with high potential of repositioning based on disease networks with the quantitative measure. Through the study, it is expected to produce profound insights for possibility of undiscovered drug repositioning.

PMID: 28539121 [PubMed - in process]

Chromone as a privileged scaffold in drug discovery - recent advances.

J Med Chem. 2017 May 24;:

Authors: Reis J, Gaspar A, Milhazes N, Borges FM

Abstract
The use of privileged structures in drug discovery has proven to be an effective strategy allowing the generation of innovative hits/leads and successful optimization processes. Chromone is actually recognized as a privileged structure and a valid template for the design of novel compounds with potential pharmacological interest, particularly in the field of neurodegenerative, inflammatory and infectious diseases as well as diabetes and cancer. Within this framework, this review provides the reader with a literature update following the preceding article entitled Chromone: a valid scaffold in Medicinal Chemistry. The review is mainly focused on the biological interest of chromones, including those isolated from natural sources. Moreover, as drug repurposing is becoming an attractive drug discovery approach, the opening repurposing studies on chromone-based drugs are also reported.

PMID: 28537720 [PubMed - as supplied by publisher]

Scientific advice - is drug repurposing missing a trick?

Nat Rev Clin Oncol. 2017 May 23;:

Authors: Pantziarka P

PMID: 28534529 [PubMed - as supplied by publisher]

Recent trends in ZikV research: A step away from cure.

Biomed Pharmacother. 2017 May 17;91:1152-1159

Authors: Alam A, Imam N, Farooqui A, Ali S, Malik MZ, Ishrat R

Abstract
Zika virus (ZikV) is a member of the Flaviviridae virus family, genus Flavivirus has emerged as a potential threat to human health worldwide. Consequences of vertical infections includes microcephaly with brain and eye anomalies, and adult infections includes Guillain-Barrésyndrome (GBS), brain ischemia, myelitis and meningoencephalitis. To develop a better treatment, many efforts are being made, like drug-repurposing concept for FDA-approved drugs for antiviral activity are screened against ZikV infection and emerging as a promising alternative to expedite drug development and various vaccines like DNA, ZPIV, LAIV, mRNA and AGS-v vaccines have been designed and in under clinical trial phases. Moreover, few pharmacological agents like Mycophenolicacid, Niclosamide, PHA-690509, Emricasan and Bortezomib are most potent anti-ZikV candidates and highly effective single or combining treatment with these drugs. This article reviews the ZikV illness, transmission patterns, pathophysiology of disease, global efforts, challenges and the prospects for the development of vaccines and antiviral agents.

PMID: 28531943 [PubMed - as supplied by publisher]

METFORMIN: NONGLYCEMIC EFFECTS AND POTENTIAL NOVEL INDICATIONS.

Endocr Pract. 2016 Aug;22(8):999-1007

Authors: Anabtawi A, Miles JM

Abstract
OBJECTIVE: Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes because of its apparent robust effects in reducing cardiovascular risk. This review examines the current literature regarding the nonglycemic effects and potential novel indications for metformin.
METHODS: Review of the literature, with a focus on metformin use in Stage 3 chronic kidney disease (CKD-3) and heart failure (HF).
RESULTS: The United Kingdom Prospective Diabetes Study suggests that metformin reduces the risk of myocardial infarction, and more recent retrospective studies have shown an association between metformin use and a reduction in stroke, atrial fibrillation and all-cause mortality. The mechanism(s) explaining these putative benefits are not clear but may involve decreased energy intake (with attendant weight loss), improvement in lipids, and lowering of blood pressure; a literature review suggests that metformin lowers blood pressure when it is elevated, but not when it is normal. Metformin appears to be safe when given to patients with CKD-3. In addition, there is evidence that individuals with CKD-3, who are at increased cardiovascular risk, stand to benefit from metformin therapy. Lactic acidosis is an extremely remote and probably avoidable risk; measurement of plasma metformin levels and more frequent monitoring of renal function may be useful in selected patients with CKD-3 who are treated with metformin. Finally, there is evidence that metformin is safe in patients with HF; metformin therapy is associated with a reduction in newly incident HF and in HF mortality.
CONCLUSION: Metformin has a dominant position in the treatment of type 2 diabetes that is deserved due to its favorable and robust effects on cardiovascular risk.
ABBREVIATIONS: AMP = adenosine monophosphate BP = blood pressure CKD = chronic kidney disease CKD-3 = Stage 3 CKD eGFR = estimated glomerular filtration rate HDL = high-density lipoprotein HF = heart failure MAP = mean arterial pressure mVO2 = myocardial oxygen consumption T2DM = type 2 diabetes mellitus UKPDS = United Kingdom Prospective Diabetes Study.

PMID: 27579542 [PubMed - indexed for MEDLINE]

Bioinformatics and in vitro experimental analyses identify the selective therapeutic potential of interferon gamma and apigenin against cervical squamous cell carcinoma and adenocarcinoma.

Oncotarget. 2017 May 02;:

Authors: Yang PM, Chou CJ, Tseng SH, Hung CF

Abstract
The clinical management and treatment of cervical cancer, one of the most commonly diagnosed cancers and a leading cause of cancer-related female death, remains a huge challenge for researchers and health professionals. Cervical cancer can be categorized into two major subtypes: common squamous cell carcinoma (SCC) and adenocarcinoma (AC). Although it is a relatively rare histological subtype of cervical cancer, there has been a steady increase in the incidences of AC. Therefore, new strategies to treat cervical cancer are urgently needed. In this study, the potential uses of IFNγ-based therapy for cervical cancer were evaluated using bioinformatics approaches. Gene expression profiling identified that cell cycle dysregulation was a major hallmark of cervical cancer including SCC and AC subtypes, and was associated with poor clinical outcomes for cervical cancer patients. In silico and in vitro experimental analyses demonstrated that IFNγ treatment could reverse the cervical cancer hallmark and induce cell cycle arrest and apoptosis. Furthermore, we demonstrated that apigenin could enhance the anticancer activity of IFNγ in a HeLa cervical AC cell line by targeting cyclin-dependent kinase 1. Taken together, the present study suggests the selective therapeutic potential of IFNγ alone or in combination with apigenin for managing cervical SCC and AC.

PMID: 28526810 [PubMed - as supplied by publisher]

Uncovering drug mechanism of action by proteome-wide identification of drug-binding proteins.

Med Chem. 2017 May 18;:

Authors: Cui T, Hou H, Sun Y, Cang H, Wang X

Abstract
Small molecule drugs obtained from synthetic compounds or natural products show their therapeutic effects by specifically binding to one or a few target proteins and modulating their functions. In contrast, undesirable drug-protein interactions may provoke harmful side effects. Furthermore, drug-protein interactions also play roles in drug activation, transport, metabolism and regulation of drug resistance. Therefore, systematically identifying binding proteins of a drug molecule is critical for understanding the mechanism of action of the drug at molecular level. In this review, we summarize current widely-used experimental approaches for proteome-wide target identification of small molecule drugs, including affinity purification, chemical proteomics and protein thermal stability based methods. The advance of these methods will quicken the pace of target deconvolution of small molecule drugs and hold promise for drug repositioning research. Moreover, these approaches also provide a powerful arsenal for exploring the signaling pathways of small molecule second messengers, signaling lipids and other regulatory metabolites.

PMID: 28523998 [PubMed - as supplied by publisher]

Repurposing of Copper(II)-chelating drugs for the treatment of neurodegenerative diseases.

Curr Med Chem. 2017 May 17;:

Authors: Lanza V, Milardi D, Di Natale G, Pappalardo G

Abstract
BACKGROUND: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews has exhaustively described either the molecular or clinical aspects of neurodegenerative diseases as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can be also effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) interacting molecules as potential drug candidates in neurodegeneration.
METHODS: Starting from the well-known harmful relationships existing between the dys-homeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, that deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature data bases and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) interacting features of the selected drugs.
RESULTS: Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis is crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repositioning copper(II) interacting drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repositioning, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease.
CONCLUSIONS: In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over de novo drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials.

PMID: 28521682 [PubMed - as supplied by publisher]

Large-scale data-driven integrative framework for extracting essential targets and processes from disease-associated gene data sets.

Brief Bioinform. 2017 May 18;:

Authors: Mazandu GK, Chimusa ER, Rutherford K, Zekeng EG, Gebremariam ZZ, Onifade MY, Mulder NJ

Abstract
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure. This failure is often because of the use of irrelevant targets identified in the early steps of the drug discovery process, suggesting that target identification and validation are cornerstones for the success of drug discovery and development. Here, we present a large-scale data-driven integrative computational framework to extract essential targets and processes from an existing disease-associated data set and enhance target selection by leveraging drug-target-disease association at the systems level. We applied this framework to tuberculosis and Ebola virus diseases combining heterogeneous data from multiple sources, including protein-protein functional interaction, functional annotation and pharmaceutical data sets. Results obtained demonstrate the effectiveness of the pipeline, leading to the extraction of essential drug targets and to the rational use of existing approved drugs. This provides an opportunity to move toward optimal target-based strategies for screening available drugs and for drug discovery. There is potential for this model to bridge the gap in the production of orphan disease therapies, offering a systematic approach to predict new uses for existing drugs, thereby harnessing their full therapeutic potential.

PMID: 28520909 [PubMed - as supplied by publisher]

Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-β-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease.

Bioorg Med Chem Lett. 2017 May 05;:

Authors: Bi Y, Might M, Vankayalapati H, Kuberan B

Abstract
N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears. Unfortunately, there has not been any therapeutic option available for this rare disease so far. Recently, a proposed molecular mechanism for NGLY1 deficiency suggested that endo-β-N-acetylglucosaminidase (ENGase) inhibitors may be promising therapeutics for NGLY1 patients. Herein, we performed structure-based virtual screening utilizing FDA-approved drug database on this ENGase target to enable repurposing of existing drugs. Several Proton Pump Inhibitors (PPIs), a series of substituted 1H-benzo [d] imidazole, and 1H-imidazo [4,5-b] pyridines, among other scaffolds, have been identified as potent ENGase inhibitors. An electrophoretic mobility shift assay was employed to assess the inhibition of ENGase activity by these PPIs. Our efforts led to the discovery of Rabeprazole Sodium as the most promising hit with an IC50 of 4.47±0.44μM. This is the first report that describes the discovery of small molecule ENGase inhibitors, which can potentially be used for the treatment of human NGLY1 deficiency.

PMID: 28512024 [PubMed - as supplied by publisher]

Inhibitors of Cancer Stem Cells.

Anticancer Agents Med Chem. 2016;16(10):1230-9

Authors: García-Rubiño ME, Lozano-López C, Campos JM

Abstract
The cancer stem cell (CSC) theory is current strategy of cancer treatment. Cancers follow pathways of cancer stem cell such as Notch, Wnt and Hedgehog can be addressed with natural products or synthetic drugs to diminish the chance of new tumours. The cancer growth can also be suppressed by aiming the tumourigenic stem cells alone, instead of targeting at reducing complete tumour dimension. The recurrence of tumours after years of disease-free survival has prompted interest in the concept that cancers may have a stem cell basis. Current assumption holds that < 5% of the tumour mass may be chemo-resistant and radio-resistant, harbouring stem-like properties that impel tumour survival, development, and metastasis. There is intense an investigation to interpret CSCs based on self-renewal and multi-lineage differentiation. Nevertheless, no successful targeted therapies have reached the clinic. The ionophore antibiotic salinomycin that selectively kills breast CSCs seems to be a promising anticancer drug. Clinical trials conducted by the NIH (National Institute of Health) on several synthetic drugs demonstrate the current importance of the issue and predict a bright future for such molecular weapons against cancer.

PMID: 27025655 [PubMed - indexed for MEDLINE]

Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1.

Oncotarget. 2017 Apr 27;:

Authors: Zheng M, Sun W, Gao S, Luan S, Li D, Chen R, Zhang Q, Chen L, Huang J, Li H

Abstract
Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstrated that clomifene inhibited mutant enzyme in a non-competitive manner. Moreover, knockdown of mutant IDH1 in HT1080 cells decreased the sensitivity to clomifene. In vivo studies indicated that clomifene significantly suppressed the tumor growth of HT1080-bearing CB-17/Icr-scid mice with oral administration of 100 mg/kg and 50 mg/kg per day. In short, our findings highlight clomifene may have clinical potential in tumor therapies as a safe and effective inhibitor of mutant IDH1.

PMID: 28498812 [PubMed - as supplied by publisher]

Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview.

Adv Ther. 2017 May 08;:

Authors: Wen WX, Lee SY, Siang R, Koh RY

Abstract
Fibrosis is a potentially debilitating disease with high morbidity rates. It is estimated that half of all deaths that occur in the USA are attributed to fibrotic disorders. Fibrotic disorders are characterized primarily by disruption in the extracellular matrix deposition and breakdown equilibrium, leading to the accumulation of excessive amounts of extracellular matrix. Given the potentially high prevalence of fibrosis and the paucity of agents currently available for the treatment of this disease, there is an urgent need for the identification of drugs that can be utilized to treat the disease. Pentoxifylline is a methylxanthine derivative that is currently approved for the treatment of vascular diseases, in particular, claudication. Pentoxifylline has three main properties: improving the rheological properties of blood, anti-inflammatory, and antioxidative. Recently, the effectiveness of pentoxifylline in the treatment of fibrosis via attenuating and reversing fibrotic lesions has been demonstrated in several clinical trials and animal studies. As a result of the limited availability of antifibrotic agents in the long-term treatment of fibrosis that can attenuate and even reverse fibrotic lesions effectively, it would be of particular importance to consider the potential clinical utility of pentoxifylline in the treatment of fibrosis. Thus, this paper discusses the evolving roles of pentoxifylline in the treatment of different types of fibrosis.

PMID: 28484954 [PubMed - as supplied by publisher]

Pediatric Drug Nitazoxanide: A Potential Choice for Control of Zika.

Open Forum Infect Dis. 2017;4(1):ofx009

Authors: Cao RY, Xu YF, Zhang TH, Yang JJ, Yuan Y, Hao P, Shi Y, Zhong J, Zhong W

Abstract
Zika virus (ZIKV) infection can be the cause of congenital malformations, including microcephaly in infants and can cause other disorders such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, which can also occur in some infected adults. However, at this time, there is no drug approved to treat ZIKV infection. Drug repurposing is the promptest way to obtain an effective drug during a global public health emergency such as the spread of Zika virus. In this study, we report a US Food and Drug Admistration-approved drug that is safe for pediatric use. Nitazoxanide and its bioactive metabolite, tizoxanide, have anti-ZIKV potential in vitro, and we identified that they exerts antiviral effect possibly by targeting the viral postattachment step.

PMID: 28480282 [PubMed - in process]

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Biochem Biophys Res Commun. 2017 May 02;:

Authors: Xiao ZX, Chen RQ, Hu DX, Xie XQ, Yu SB, Chen XQ

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

PMID: 28476618 [PubMed - as supplied by publisher]

In vitro activity of the antiasthmatic drug zafirlukast against the oral pathogens Porphyromonas gingivalis and Streptococcus mutans.

FEMS Microbiol Lett. 2017 Jan 01;364(2):

Authors: Gerits E, Van der Massen I, Vandamme K, De Cremer K, De Brucker K, Thevissen K, Cammue BPA, Beullens S, Fauvart M, Verstraeten N, Michiels J, Roberts M

Abstract
Oral infections are among the most common diseases worldwide. Many protocols for the prevention and treatment of oral infections have been described, yet no golden standard has been developed so far. The antiseptic chlorhexidine and antibiotics are often used in these treatment procedures. However, long-term use of chlorhexidine can lead to side effects and extensive use of antibiotics can promote the development of antibiotic-resistant bacteria, which in turn can compromise the effectiveness of the treatment. Consequently, it remains important to search for new antibacterial agents for the treatment of oral infections. In this study, we report on the antibacterial activity of the antiasthma drug zafirlukast against oral pathogens Porphyromonas gingivalis and Streptococcus mutans. Furthermore, its activity against oral biofilms grown on titanium surfaces was confirmed. In addition, we demonstrated that zafirlukast displays no cytotoxicity against human osteoblasts. Combined, this study paves the way for further research to determine the potential of zafirlukast to be used as a new antibiotic against oral pathogens.

PMID: 28087617 [PubMed - indexed for MEDLINE]

Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii.

J Antibiot (Tokyo). 2016 Jun;69(6):415-21

Authors: Tran TB, Cheah SE, Yu HH, Bergen PJ, Nation RL, Creek DJ, Purcell A, Forrest A, Doi Y, Song J, Velkov T, Li J

Abstract
Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii. However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of polymyxin B with anthelmintic closantel against A. baumannii. Closantel monotherapy (16 mg l(-1)) was ineffective against most tested A. baumannii isolates. However, closantel at 4-16 mg l(-1) with a clinically achievable concentration of polymyxin B (2 mg l(-1)) successfully inhibited the development of polymyxin resistance in polymyxin-susceptible isolates, and provided synergistic killing against polymyxin-resistant isolates (MIC ⩾4 mg l(-1)). Our findings suggest that the combination of polymyxin B with closantel could be potentially useful for the treatment of MDR, including polymyxin-resistant, A. baumannii infections. The repositioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial 'superbugs'.

PMID: 26669752 [PubMed - indexed for MEDLINE]