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Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes
Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associat...
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| Published in: | PloS one 2013-11, Vol.8 (11), p.e78822-e78822 |
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| creator | Moore, Aimée M Patel, Sanket Forsberg, Kevin J Wang, Bin Bentley, Gayle Razia, Yasmin Qin, Xuan Tarr, Phillip I Dantas, Gautam |
| description | Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracycline-resistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic pressure in the human host, and that cryptic gut microbes are an important resistance reservoir. The observed transferability of gut-associated resistance genes to a gram-negative (E. coli) host also suggests that the potential for gut-associated resistomes to threaten human health by mediating antibiotic resistance in pathogens warrants further investigation. |
| doi_str_mv | 10.1371/journal.pone.0078822 |
| format | article |
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Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracycline-resistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic pressure in the human host, and that cryptic gut microbes are an important resistance reservoir. The observed transferability of gut-associated resistance genes to a gram-negative (E. coli) host also suggests that the potential for gut-associated resistomes to threaten human health by mediating antibiotic resistance in pathogens warrants further investigation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0078822</identifier><identifier>PMID: 24236055</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adolescent ; Aminoglycoside antibiotics ; Anti-Bacterial Agents - pharmacology ; Antibacterial agents ; Antibiotic resistance ; Antibiotics ; Antimicrobial agents ; Bacteria ; Bacteroides - genetics ; Beta lactamases ; Biology ; Child ; Child, Preschool ; Children ; Chloramphenicol ; Clostridium - genetics ; Computer applications ; Deoxyribonucleic acid ; Dihydrofolate reductase ; DNA ; Drug resistance ; Drug Resistance, Bacterial - genetics ; E coli ; Efflux ; Enterobacter - genetics ; Epidemiology ; Escherichia coli ; Fecal microflora ; Feces ; Feces - microbiology ; Female ; Folic acid ; Genes ; Genes, Bacterial ; Genetic engineering ; Genomes ; Health risks ; Humans ; Hydrolase ; Immunology ; Infant ; Infants ; Intestinal microflora ; Laboratories ; Likelihood Functions ; Male ; Medicine ; Methylase ; Methyltransferases ; Microbial drug resistance ; Microbiota ; Microbiota (Symbiotic organisms) ; Microbiota - genetics ; Molecular Sequence Annotation ; Nucleotide sequence ; Pathology ; Pediatrics ; Phylogeny ; Proteins ; Reductases ; Regulators ; RNA ; rRNA (adenosine-2'-0'-)-methyltransferase ; rRNA 16S ; Sequence Analysis, DNA ; Stools ; Streptococcus infections ; Synthesis ; Teenagers ; Transcription ; Transcription (Genetics) ; Transporter ; Young Adult ; β Lactamase</subject><ispartof>PloS one, 2013-11, Vol.8 (11), p.e78822-e78822</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Moore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Moore et al 2013 Moore et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-e8f2ce2554d9c55bdfd566bf660e9bf507f87d0c866927097fa6dee916deea893</citedby><cites>FETCH-LOGICAL-c692t-e8f2ce2554d9c55bdfd566bf660e9bf507f87d0c866927097fa6dee916deea893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1458259498/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1458259498?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24236055$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tse, Herman</contributor><creatorcontrib>Moore, Aimée M</creatorcontrib><creatorcontrib>Patel, Sanket</creatorcontrib><creatorcontrib>Forsberg, Kevin J</creatorcontrib><creatorcontrib>Wang, Bin</creatorcontrib><creatorcontrib>Bentley, Gayle</creatorcontrib><creatorcontrib>Razia, Yasmin</creatorcontrib><creatorcontrib>Qin, Xuan</creatorcontrib><creatorcontrib>Tarr, Phillip I</creatorcontrib><creatorcontrib>Dantas, Gautam</creatorcontrib><title>Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracycline-resistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic pressure in the human host, and that cryptic gut microbes are an important resistance reservoir. The observed transferability of gut-associated resistance genes to a gram-negative (E. coli) host also suggests that the potential for gut-associated resistomes to threaten human health by mediating antibiotic resistance in pathogens warrants further investigation.</description><subject>Adolescent</subject><subject>Aminoglycoside antibiotics</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial agents</subject><subject>Antibiotic resistance</subject><subject>Antibiotics</subject><subject>Antimicrobial agents</subject><subject>Bacteria</subject><subject>Bacteroides - genetics</subject><subject>Beta lactamases</subject><subject>Biology</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Children</subject><subject>Chloramphenicol</subject><subject>Clostridium - genetics</subject><subject>Computer applications</subject><subject>Deoxyribonucleic acid</subject><subject>Dihydrofolate reductase</subject><subject>DNA</subject><subject>Drug resistance</subject><subject>Drug Resistance, Bacterial - genetics</subject><subject>E coli</subject><subject>Efflux</subject><subject>Enterobacter - genetics</subject><subject>Epidemiology</subject><subject>Escherichia coli</subject><subject>Fecal microflora</subject><subject>Feces</subject><subject>Feces - microbiology</subject><subject>Female</subject><subject>Folic acid</subject><subject>Genes</subject><subject>Genes, Bacterial</subject><subject>Genetic engineering</subject><subject>Genomes</subject><subject>Health risks</subject><subject>Humans</subject><subject>Hydrolase</subject><subject>Immunology</subject><subject>Infant</subject><subject>Infants</subject><subject>Intestinal microflora</subject><subject>Laboratories</subject><subject>Likelihood Functions</subject><subject>Male</subject><subject>Medicine</subject><subject>Methylase</subject><subject>Methyltransferases</subject><subject>Microbial drug 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Premium</collection><collection>ProQuest Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest - Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Open Access: DOAJ - Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moore, Aimée M</au><au>Patel, Sanket</au><au>Forsberg, Kevin J</au><au>Wang, Bin</au><au>Bentley, Gayle</au><au>Razia, Yasmin</au><au>Qin, Xuan</au><au>Tarr, Phillip I</au><au>Dantas, Gautam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-11-13</date><risdate>2013</risdate><volume>8</volume><issue>11</issue><spage>e78822</spage><epage>e78822</epage><pages>e78822-e78822</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Conceived and designed the experiments: AMM PIT GD. Performed the experiments: AMM SP BW GB. Analyzed the data: AMM SP KJF GD. Contributed reagents/materials/analysis tools: YR XQ PIT. Wrote the paper: AMM GD PIT.</notes><notes>Competing Interests: The authors have declared that no competing interests exist.</notes><abstract>Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracycline-resistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic pressure in the human host, and that cryptic gut microbes are an important resistance reservoir. The observed transferability of gut-associated resistance genes to a gram-negative (E. coli) host also suggests that the potential for gut-associated resistomes to threaten human health by mediating antibiotic resistance in pathogens warrants further investigation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24236055</pmid><doi>10.1371/journal.pone.0078822</doi><tpages>e78822</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-11, Vol.8 (11), p.e78822-e78822 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1458259498 |
| source | Open Access: PubMed Central; ProQuest - Publicly Available Content Database |
| subjects | Adolescent Aminoglycoside antibiotics Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotic resistance Antibiotics Antimicrobial agents Bacteria Bacteroides - genetics Beta lactamases Biology Child Child, Preschool Children Chloramphenicol Clostridium - genetics Computer applications Deoxyribonucleic acid Dihydrofolate reductase DNA Drug resistance Drug Resistance, Bacterial - genetics E coli Efflux Enterobacter - genetics Epidemiology Escherichia coli Fecal microflora Feces Feces - microbiology Female Folic acid Genes Genes, Bacterial Genetic engineering Genomes Health risks Humans Hydrolase Immunology Infant Infants Intestinal microflora Laboratories Likelihood Functions Male Medicine Methylase Methyltransferases Microbial drug resistance Microbiota Microbiota (Symbiotic organisms) Microbiota - genetics Molecular Sequence Annotation Nucleotide sequence Pathology Pediatrics Phylogeny Proteins Reductases Regulators RNA rRNA (adenosine-2'-0'-)-methyltransferase rRNA 16S Sequence Analysis, DNA Stools Streptococcus infections Synthesis Teenagers Transcription Transcription (Genetics) Transporter Young Adult β Lactamase |
| title | Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes |
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