Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

Clin Transplant. 2015 Dec;29(12):1213-20

Authors: Lesche D, Sigurdardottir V, Setoud R, Englberger L, Fiedler GM, Largiadèr CR, Mohacsi P, Sistonen J

Abstract
BACKGROUND: Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients.
METHODS: Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts.
RESULTS: While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction.
CONCLUSION: Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability.

PMID: 26458301 [PubMed - indexed for MEDLINE]

The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

Neuromuscul Disord. 2015 Dec;25(12):955-8

Authors: Ke Q, He F, Lu L, Yu P, Jiang Y, Weng C, Huang H, Yi X, Qi M

Abstract
Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis.

PMID: 26433613 [PubMed - indexed for MEDLINE]

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes.

Br J Clin Pharmacol. 2016 Feb;81(2):301-12

Authors: Kim HS, Lim Y, Oh M, Ghim JL, Kim EY, Kim DH, Shin JG

Abstract
AIM: The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes.
METHODS: In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment.
RESULTS: The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects.
CONCLUSIONS: The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects.

PMID: 26426352 [PubMed - indexed for MEDLINE]

Recent Advances and Emerging Applications in Text and Data Mining for Biomedical Discovery.

Brief Bioinform. 2016 Jan;17(1):33-42

Authors: Gonzalez GH, Tahsin T, Goodale BC, Greene AC, Greene CS

Abstract
Precision medicine will revolutionize the way we treat and prevent disease. A major barrier to the implementation of precision medicine that clinicians and translational scientists face is understanding the underlying mechanisms of disease. We are starting to address this challenge through automatic approaches for information extraction, representation and analysis. Recent advances in text and data mining have been applied to a broad spectrum of key biomedical questions in genomics, pharmacogenomics and other fields. We present an overview of the fundamental methods for text and data mining, as well as recent advances and emerging applications toward precision medicine.

PMID: 26420781 [PubMed - indexed for MEDLINE]

Modelling and extraction of variability in free-text medication prescriptions from an anonymised primary care electronic medical record research database.

BMC Med Inform Decis Mak. 2016 Feb 09;16:18

Authors: Karystianis G, Sheppard T, Dixon WG, Nenadic G

Abstract
BACKGROUND: Free-text medication prescriptions contain detailed instruction information that is key when preparing drug data for analysis. The objective of this study was to develop a novel model and automated text-mining method to extract detailed structured medication information from free-text prescriptions and explore their variability (e.g. optional dosages) in primary care research databases.
METHODS: We introduce a prescription model that provides minimum and maximum values for dose number, frequency and interval, allowing modelling variability and flexibility within a drug prescription. We developed a text mining system that relies on rules to extract such structured information from prescription free-text dosage instructions. The system was applied to medication prescriptions from an anonymised primary care electronic record database (Clinical Practice Research Datalink, CPRD).
RESULTS: We have evaluated our approach on a test set of 220 CPRD prescription free-text directions. The system achieved an overall accuracy of 91 % at the prescription level, with 97 % accuracy across the attribute levels. We then further analysed over 56,000 most common free text prescriptions from CPRD records and found that 1 in 4 has inherent variability, i.e. a choice in taking medication specified by different minimum and maximum doses, duration or frequency.
CONCLUSIONS: Our approach provides an accurate, automated way of coding prescription free text information, including information about flexibility and variability within a prescription. The method allows the researcher to decide how best to prepare the prescription data for drug efficacy and safety analyses in any given setting, and test various scenarios and their impact.

PMID: 26860263 [PubMed - indexed for MEDLINE]

Recent Advances and Emerging Applications in Text and Data Mining for Biomedical Discovery.

Brief Bioinform. 2016 Jan;17(1):33-42

Authors: Gonzalez GH, Tahsin T, Goodale BC, Greene AC, Greene CS

Abstract
Precision medicine will revolutionize the way we treat and prevent disease. A major barrier to the implementation of precision medicine that clinicians and translational scientists face is understanding the underlying mechanisms of disease. We are starting to address this challenge through automatic approaches for information extraction, representation and analysis. Recent advances in text and data mining have been applied to a broad spectrum of key biomedical questions in genomics, pharmacogenomics and other fields. We present an overview of the fundamental methods for text and data mining, as well as recent advances and emerging applications toward precision medicine.

PMID: 26420781 [PubMed - indexed for MEDLINE]

Community challenges in biomedical text mining over 10 years: success, failure and the future.

Brief Bioinform. 2016 Jan;17(1):132-44

Authors: Huang CC, Lu Z

Abstract
One effective way to improve the state of the art is through competitions. Following the success of the Critical Assessment of protein Structure Prediction (CASP) in bioinformatics research, a number of challenge evaluations have been organized by the text-mining research community to assess and advance natural language processing (NLP) research for biomedicine. In this article, we review the different community challenge evaluations held from 2002 to 2014 and their respective tasks. Furthermore, we examine these challenge tasks through their targeted problems in NLP research and biomedical applications, respectively. Next, we describe the general workflow of organizing a Biomedical NLP (BioNLP) challenge and involved stakeholders (task organizers, task data producers, task participants and end users). Finally, we summarize the impact and contributions by taking into account different BioNLP challenges as a whole, followed by a discussion of their limitations and difficulties. We conclude with future trends in BioNLP challenge evaluations.

PMID: 25935162 [PubMed - indexed for MEDLINE]

Ophthalmological manifestations of Parry-Romberg syndrome.

Surv Ophthalmol. 2016 Nov - Dec;61(6):693-701

Authors: Bucher F, Fricke J, Neugebauer A, Cursiefen C, Heindl LM

Abstract
Parry-Romberg syndrome is a rare disease characterized by slowly progressive atrophy affecting facial subcutaneous tissues, including the underlying muscles and osteocartilaginous structures. Various periocular, ocular, and neuro-ophthalmological manifestations have been described in Parry-Romberg syndrome. The most common periocular disorders include enophthalmos, eyelid, and orbit alterations. The most frequent ocular disorders include corneal and retinal changes, and the most common neuro-ophthalmological disorders involve optic nerve, ocular motor and pupillary dysfunction. Besides the characteristic facial abnormalities, systemic manifestations may occur, including neurologic, dermatologic, cardiac, endocrine, infectious, orthodontic, and maxillofacial disorders. So far, mainly brief case reports describe these ophthalmological findings. Therefore, we summarize the ocular, periocular, and neuro-ophthalmological findings in detail, describe diagnostic modalities, and outline therapeutic options.

PMID: 27045226 [PubMed - in process]

Bronchiectasis and Aspergillus: How are they linked?

Med Mycol. 2016 Oct 28;:

Authors: De Soyza A, Aliberti S

Abstract
Bronchiectasis is a chronic airway infection syndrome, distinct from cystic fibrosis that is rising in prevalence and is associated with significant morbidity and mortality. It can be caused by many etiologies including post-infectious effects or be seen in common lung diseases such as chronic obstructive pulmonary disease (COPD) or severe asthma. Bronchiectasis is associated with many Aspergillus-associated syndromes: allergic bronchopulmonary aspergillosis (ABPA) may complicate asthma, thus leading to bronchiectasis as part of the diagnostic criteria of ABPA or can complicate preexisting bronchiectasis due to another etiology. Aspergilloma can develop in areas of lung damage seen in patients with bronchiectasis, whereas fungal bronchitis may lead to later bronchiectasis. Invasive aspergillosis, perhaps more commonly viewed as a consequence of significant immunosuppression, is also seen in the absence of immunosuppression in those with underlying lung diseases including bronchiectasis. The pathogenesis and treatments of these diverse Aspergillus-associated diseases in bronchiectasis are discussed.

PMID: 27794529 [PubMed - as supplied by publisher]

Phytomedicine-Modulating oxidative stress and the tumor microenvironment for cancer therapy.

Pharmacol Res. 2016 Oct 26;:

Authors: Cheng YT, Yang CC, Shyur LF

Abstract
In spite of the current advances and achievements in systems biology and translational medicinal research, the current strategies for cancer therapy, such as radiotherapy, targeted therapy, immunotherapy and chemotherapy remain palliative or unsatisfactory due to tumor metastasis or recurrence after surgery/therapy, drug resistance, adverse side effects, and so on. Oxidative stress (OS) plays a critical role in chronic/acute inflammation, carcinogenesis, tumor progression, and tumor invasion/metastasis which is also attributed to the dynamic and complex properties and activities in the tumor microenvironment (TME). Re-educating or reprogramming tumor-associated stromal or immune cells in the TME provides an approach for restoring immune surveillance impaired by disease in cancer patients to increase overall survival and reduce drug resistance. Herbal medicines or plant-derived natural products have historically been a major source of anti-cancer drugs. Delving into the lore of herbal medicine may uncover new leads for anti-cancer drugs. Phytomedicines have been widely documented to directly or indirectly target multiple signaling pathways and networks in cancer cells. A combination of anti-cancer drugs and polypharmacological plant-derived extracts or compounds may offer a significant advantage in sensitizing the efficacy of monotherapy and overcoming drug-induced resistance in cancer patients. This review introduces several phytochemicals and phytoextracts derived from medicinal plants or dietary vegetables that have been studied for their efficacy in preclinical cancer models. We address the underlying modes of action of induction of OS and deregulation of TME-associated stromal cells, mediators and signaling pathways, and reference the related clinical investigations that look at the single or combination use of phytochemicals and phytoextracts to sensitize anti-cancer drug effects and/or overcome drug resistance.

PMID: 27794498 [PubMed - as supplied by publisher]

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/10/30

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19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/10/30

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-Sparing Potential.

J Biol Chem. 2016 Oct 28;:

Authors: Bloom J, Metz C, Nalawade S, Casabar J, Cheng KF, He M, Sherry B, Coleman T, Forsthuber T, Al-Abed Y

Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter- regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high-affinity small molecule inhibitors. Although several classes of these compounds have been identified, biological characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti- inflammatory activity, especially with regard to TNFα. We further investigated a molecule with relatively low anti- inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis (EAE), a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis.

PMID: 27793992 [PubMed - as supplied by publisher]

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.

Proc Natl Acad Sci U S A. 2016 Oct 17;:

Authors: Sisignano M, Angioni C, Park CK, Meyer Dos Santos S, Jordan H, Kuzikov M, Liu D, Zinn S, Hohman SW, Schreiber Y, Zimmer B, Schmidt M, Lu R, Suo J, Zhang DD, Schäfer SM, Hofmann M, Yekkirala AS, de Bruin N, Parnham MJ, Woolf CJ, Ji RR, Scholich K, Geisslinger G

Abstract
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.

PMID: 27791151 [PubMed - as supplied by publisher]

Targeting Phosphatidylinositol 4-Kinase IIIα for Radiosensitization: A Potential Model of Drug Repositioning Using an Anti-Hepatitis C Viral Agent.

Int J Radiat Oncol Biol Phys. 2016 Nov 15;96(4):867-876

Authors: Kwon J, Kim DH, Park JM, Park YH, Hwang YH, Wu HG, Shin KH, Kim IA

Abstract
PURPOSE: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells.
METHODS AND MATERIALS: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed.
RESULTS: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy.
CONCLUSION: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.

PMID: 27788957 [PubMed - in process]

Pharmacogenetics and ethnicity: relevance for clinical implementation, clinical trials, pharmacovigilance and drug regulation in Latin America.

Pharmacogenomics. 2016 Oct 28;

Authors: Sosa-Macías M, Teran E, Waters W, Fors MM, Altamirano C, Jung-Cook H, Galaviz-Hernández C, López-López M, Remírez D, Moya GE, Hernández F, Fariñas H, Ramírez R, Céspedes-Garro C, Tarazona-Santos E, LLerena A

Abstract
Congress of Pharmacogenetics and Personalized Medicine. Ethnicity, clinical implementation and regulatory environment (MESTIFAR 2016 Quito). Quito, Ecuador, 19-21 May 2016. The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) was created in 2006 with the main aim of promoting personalized medicine and collaborative pharmacogenetics research in Spanish- and Portuguese-speaking countries in America and the Iberian Peninsula. The final goal of this initiative was the inclusion of Latin American populations that may benefit from the implementation of personalized medicine in drug therapy. Several initiatives have been promoted including the MESTIFAR project, which aimed to analyze the ethnicity, genotype and/or metabolic phenotype in Ibero-American populations. To date, 6060 healthy volunteers have been analyzed; among them, 2571 were admixed, 1824 were Caucasians, 1395 were Native Americans, 174 were Jews and 96 were Afro-descendants. Due to the large genetic variability within Latin Americans, ethnicity may be a relevant factor for the clinical implementation of personalized medicine. Moreover, the present status of clinical implementation and the future perspectives of pharmacogenetics, pharmacovigilance and clinical trials for drug regulation in Latin America compared with the EMA-Pharmacogenomics Working Party and the US FDA initiatives were analyzed.

PMID: 27790935 [PubMed - as supplied by publisher]

The path to implementation of personalized medicine of aromatase inhibitors in patients with breast cancer.

Pharmacogenomics. 2016 Oct 28;

Authors: Liu X, Beith J, Low SK, Boddy AV

PMID: 27790931 [PubMed - as supplied by publisher]

Pharmacogenomics education and research at the Department of Pharmacy, University of Patras, Greece.

Pharmacogenomics. 2016 Oct 28;

Authors: Patrinos GP, Katsila T

Abstract
The Pharmacogenomics and Personalized Medicine group belongs to the Laboratory of Molecular Biology and Immunology, Department of Pharmacy and is active since 2009 mainly in the field of pharmacogenomics and personalized medicine. Herein, we describe the research interests, collaborations and accomplishments of the Pharmacogenomics and Personalized Medicine group together with the teaching activities of the group that greatly enhance the pharmacogenomics knowledge of graduate/postgraduate students and healthcare professionals.

PMID: 27790924 [PubMed - as supplied by publisher]

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: A systematic review.

Clin Exp Allergy. 2016 Oct 27;:

Authors: Farzan N, Vijverberg SJ, Arets HG, Raaijmakers JA, Maitland-van der Zee AH

Abstract
BACKGROUND: Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remain limited.
OBJECTIVE: To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in asthmatic patients.
METHODS: Articles published between 1999 and June 2015 were searched using PubMed and Embase. Pharmacogenomics/genetics studies of asthmatic patients using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of SNPs that had been replicated at least once were assessed in more detail.
RESULTS: In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two Genome-Wide Association Studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This Single Nucleotide Polymorphism [SNP] was associated with all three outcomes of poor response and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51).
CONCLUSION & CLINICAL RELEVANCE: There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene (encoding for a low affinity IgE receptor (CD23)) and poor ICS response. Larger studies with well phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics. This article is protected by copyright. All rights reserved.

PMID: 27790783 [PubMed - as supplied by publisher]

Enabling techniques in the search for new antibiotics: combinatorial biosynthesis of sugar-containing antibiotics.

Biochem Pharmacol. 2016 Oct 25;:

Authors: Won Park J, Nam SJ, Joon Yoon Y

Abstract
Nature has a talent for inventing a vast number of natural products, including hybrids generated by blending different scaffolds, resulting in a myriad of bioactive chemical entities. Herein, we review the highlights and recent trends (2010 to 2016) in the combinatorial biosynthesis of sugar-containing antibiotics where nature's structural diversification capabilities are exploited to enable the creation of new anti-infective and anti-proliferative drugs. In this review, we describe the modern combinatorial biosynthetic approaches for polyketide synthase-derived complex and aromatic polyketides, non-ribosomal peptide synthetase-directed lipo-/glycopeptides, aminoglycosides, nucleoside antibiotics, and alkaloids, along with their therapeutic potential. Finally, we present the feasible nexus between combinatorial biosynthesis, systems biology, and synthetic biology as a toolbox to provide new antibiotics that will be indispensable in the post-antibiotic era.

PMID: 27793719 [PubMed - as supplied by publisher]