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      The Human Gut Antibiotic Resistome in the Metagenomic Era: Progress and Perspectives

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          Abstract

          The human gut is populated by a vast number of bacteria, which play a critical role in human health. In recent years, attention has focused on the gut bacteria as a reservoir of antibiotic resistance genes (ARGs). Both culture-dependent and culture-independent methods have been applied to investigate numerous ARGs, collectively called the antibiotic resistome, harbored by gut bacteria. This has led to an increased understanding of the overall profile of the gut antibiotic resistome, although it remains incompletely understood. In this review, we summarize the recent research findings on the human gut antibiotic resistome, with an emphasis on progress achieved using the culture-independent metagenomic strategy. We also describe the features of different available ARG databases used for annotation in metagenomic analysis, discuss the potential problems and limitations in current research, and suggest several directions for future investigation.

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          Most cited references44

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          The comprehensive antibiotic resistance database.

          The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.
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            Metagenomics: application of genomics to uncultured microorganisms.

            Metagenomics (also referred to as environmental and community genomics) is the genomic analysis of microorganisms by direct extraction and cloning of DNA from an assemblage of microorganisms. The development of metagenomics stemmed from the ineluctable evidence that as-yet-uncultured microorganisms represent the vast majority of organisms in most environments on earth. This evidence was derived from analyses of 16S rRNA gene sequences amplified directly from the environment, an approach that avoided the bias imposed by culturing and led to the discovery of vast new lineages of microbial life. Although the portrait of the microbial world was revolutionized by analysis of 16S rRNA genes, such studies yielded only a phylogenetic description of community membership, providing little insight into the genetics, physiology, and biochemistry of the members. Metagenomics provides a second tier of technical innovation that facilitates study of the physiology and ecology of environmental microorganisms. Novel genes and gene products discovered through metagenomics include the first bacteriorhodopsin of bacterial origin; novel small molecules with antimicrobial activity; and new members of families of known proteins, such as an Na(+)(Li(+))/H(+) antiporter, RecA, DNA polymerase, and antibiotic resistance determinants. Reassembly of multiple genomes has provided insight into energy and nutrient cycling within the community, genome structure, gene function, population genetics and microheterogeneity, and lateral gene transfer among members of an uncultured community. The application of metagenomic sequence information will facilitate the design of better culturing strategies to link genomic analysis with pure culture studies.
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              ARDB—Antibiotic Resistance Genes Database

              The treatment of infections is increasingly compromised by the ability of bacteria to develop resistance to antibiotics through mutations or through the acquisition of resistance genes. Antibiotic resistance genes also have the potential to be used for bio-terror purposes through genetically modified organisms. In order to facilitate the identification and characterization of these genes, we have created a manually curated database—the Antibiotic Resistance Genes Database (ARDB)—unifying most of the publicly available information on antibiotic resistance. Each gene and resistance type is annotated with rich information, including resistance profile, mechanism of action, ontology, COG and CDD annotations, as well as external links to sequence and protein databases. Our database also supports sequence similarity searches and implements an initial version of a tool for characterizing common mutations that confer antibiotic resistance. The information we provide can be used as compendium of antibiotic resistance factors as well as to identify the resistance genes of newly sequenced genes, genomes, or metagenomes. Currently, ARDB contains resistance information for 13 293 genes, 377 types, 257 antibiotics, 632 genomes, 933 species and 124 genera. ARDB is available at http://ardb.cbcb.umd.edu/.
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                Author and article information

                Contributors
                Journal
                Infectious Diseases and Translational Medicine
                Infect. Dis. Transl. Med.
                Infect. Dis. Transl. Med.
                International Biological and Medical Journals Publishing House Co., Limited (Room E16, 3/f, Yongda Commercial Building, No.97, Bonham Stand (Sheung Wan), HongKong )
                2411-2917
                10 April 2016
                10 April 2016
                : 2
                : 1
                : 41-47
                Affiliations
                From CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, China; Beijing Key Laboratory of Microbial Drug Resistance and Resistome, Beijing 100101, China
                From CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, China; Beijing Key Laboratory of Microbial Drug Resistance and Resistome, Beijing 100101, China
                Author notes
                Correspondence to: Baoli Zhu, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Tel: +86-10-6480-7362, Fax: +86-10-6480-7358, Email: zhubaoli@ 123456im.ac.cn .
                Article
                10.11979/idtm.201601006
                54d2b4b6-b7c3-40fa-82e2-aa773b52ef86

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Page count
                Figures: 1, Tables: 1, References: 53, Pages: 7
                Product
                Categories
                Review

                Medicine,Infectious disease & Microbiology
                Antibiotic resistance gene,Horizontal gene transfer,Antibiotic resistome,Human gut microbiome,Metagenomics

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