In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens
The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab10...
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| Veröffentlicht in: | Scientific reports 2020-04, Vol.10 (1), p.7163-7163, Article 7163 |
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| creator | Blasco, Lucia Ambroa, Anton Trastoy, Rocio Bleriot, Ines Moscoso, Miriam Fernández-Garcia, Laura Perez-Nadales, Elena Fernández-Cuenca, Felipe Torre-Cisneros, Julian Oteo-Iglesias, Jesus Oliver, Antonio Canton, Rafael Kidd, Tim Navarro, Ferran Miró, Elisenda Pascual, Alvaro Bou, German Martínez-Martínez, Luis Tomas, Maria |
| description | The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates (
Acinetobacter baumannii
,
Pseudomonas aeruginosa
and
Klebsiella pneumoniae
) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of
A. baumannii
and
P. aeruginosa
tested and against 13 out of 17 strains of
K. pneumoniae
. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except
K. pneumoniae
. These results were confirmed
in vivo
in
G. mellonella
survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both
in vitro
and
in vivo
studies. This will potentially enable reduction of the dose of colistin used in clinical practice. |
| doi_str_mv | 10.1038/s41598-020-64145-7 |
| format | Article |
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Acinetobacter baumannii
,
Pseudomonas aeruginosa
and
Klebsiella pneumoniae
) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of
A. baumannii
and
P. aeruginosa
tested and against 13 out of 17 strains of
K. pneumoniae
. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except
K. pneumoniae
. These results were confirmed
in vivo
in
G. mellonella
survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both
in vitro
and
in vivo
studies. This will potentially enable reduction of the dose of colistin used in clinical practice.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-64145-7</identifier><identifier>PMID: 32346029</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154 ; 631/326 ; Antimicrobial activity ; Antimicrobial agents ; Bactericidal activity ; Bronchopulmonary infection ; Clinical isolates ; Colistin ; Colistin - pharmacology ; Drug resistance ; Drug Resistance, Multiple, Bacterial - drug effects ; Endopeptidases - pharmacology ; Genomes ; Gram-Negative Bacteria - growth & development ; Humanities and Social Sciences ; Klebsiella pneumoniae ; Microbial Sensitivity Tests ; Minimum inhibitory concentration ; multidisciplinary ; Multidrug resistance ; Phages ; Science ; Science (multidisciplinary) ; Strains (organisms) ; Turbidity</subject><ispartof>Scientific reports, 2020-04, Vol.10 (1), p.7163-7163, Article 7163</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-2dac29f0970dd3c6786845ac7614289e0323d6f8350a44f7446db93f0543877f3</citedby><cites>FETCH-LOGICAL-c511t-2dac29f0970dd3c6786845ac7614289e0323d6f8350a44f7446db93f0543877f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188820/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188820/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32346029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Blasco, Lucia</creatorcontrib><creatorcontrib>Ambroa, Anton</creatorcontrib><creatorcontrib>Trastoy, Rocio</creatorcontrib><creatorcontrib>Bleriot, Ines</creatorcontrib><creatorcontrib>Moscoso, Miriam</creatorcontrib><creatorcontrib>Fernández-Garcia, Laura</creatorcontrib><creatorcontrib>Perez-Nadales, Elena</creatorcontrib><creatorcontrib>Fernández-Cuenca, Felipe</creatorcontrib><creatorcontrib>Torre-Cisneros, Julian</creatorcontrib><creatorcontrib>Oteo-Iglesias, Jesus</creatorcontrib><creatorcontrib>Oliver, Antonio</creatorcontrib><creatorcontrib>Canton, Rafael</creatorcontrib><creatorcontrib>Kidd, Tim</creatorcontrib><creatorcontrib>Navarro, Ferran</creatorcontrib><creatorcontrib>Miró, Elisenda</creatorcontrib><creatorcontrib>Pascual, Alvaro</creatorcontrib><creatorcontrib>Bou, German</creatorcontrib><creatorcontrib>Martínez-Martínez, Luis</creatorcontrib><creatorcontrib>Tomas, Maria</creatorcontrib><title>In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates (
Acinetobacter baumannii
,
Pseudomonas aeruginosa
and
Klebsiella pneumoniae
) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of
A. baumannii
and
P. aeruginosa
tested and against 13 out of 17 strains of
K. pneumoniae
. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except
K. pneumoniae
. These results were confirmed
in vivo
in
G. mellonella
survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both
in vitro
and
in vivo
studies. This will potentially enable reduction of the dose of colistin used in clinical practice.</description><subject>631/154</subject><subject>631/326</subject><subject>Antimicrobial activity</subject><subject>Antimicrobial agents</subject><subject>Bactericidal activity</subject><subject>Bronchopulmonary infection</subject><subject>Clinical isolates</subject><subject>Colistin</subject><subject>Colistin - pharmacology</subject><subject>Drug resistance</subject><subject>Drug Resistance, Multiple, Bacterial - drug effects</subject><subject>Endopeptidases - pharmacology</subject><subject>Genomes</subject><subject>Gram-Negative Bacteria - growth & development</subject><subject>Humanities and Social Sciences</subject><subject>Klebsiella pneumoniae</subject><subject>Microbial Sensitivity Tests</subject><subject>Minimum inhibitory concentration</subject><subject>multidisciplinary</subject><subject>Multidrug resistance</subject><subject>Phages</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Strains (organisms)</subject><subject>Turbidity</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU1rFTEUhoMottT-ARcScONmNJ8zmY0gRW2h4EbXITcf05RMck0yF-6P6H8247S1ujCbfJznfXMOLwCvMXqPERUfCsN8FB0iqOsZZrwbnoFTgtqBUEKePzmfgPNSblFbnIwMjy_BCSWU9YiMp-DuKsKDrzlBFQ306-WQoHXOa6WPMDmo07zzUVWfYtnuwZfayFVgvHM221ihjSaFY_ENUpNqW4U6-NhsAiw1ry-rel5C9Z3JywSzLc1INe1e1Zs02VhegRdOhWLP7_cz8OPL5-8Xl931t69XF5-uO80xrh0xSpPRoXFAxlDdD6IXjCs99JgRMVrU5jO9E5QjxZgbGOvNbqQOcUbFMDh6Bj5uvvtlN1uj2wBZBbnPflb5KJPy8u9K9DdySgc5YCEEQc3g3b1BTj8XW6qcfdE2BBVtWookdOwp6jlb0bf_oLdpybGNt1K8tUQFaxTZKJ1TKdm6x2YwkmvgcgtctsDl78Dl0ERvno7xKHmItwF0A0orxcnmP3__x_YXia24pw</recordid><startdate>20200428</startdate><enddate>20200428</enddate><creator>Blasco, Lucia</creator><creator>Ambroa, Anton</creator><creator>Trastoy, Rocio</creator><creator>Bleriot, Ines</creator><creator>Moscoso, Miriam</creator><creator>Fernández-Garcia, Laura</creator><creator>Perez-Nadales, Elena</creator><creator>Fernández-Cuenca, Felipe</creator><creator>Torre-Cisneros, Julian</creator><creator>Oteo-Iglesias, Jesus</creator><creator>Oliver, Antonio</creator><creator>Canton, Rafael</creator><creator>Kidd, Tim</creator><creator>Navarro, Ferran</creator><creator>Miró, Elisenda</creator><creator>Pascual, Alvaro</creator><creator>Bou, German</creator><creator>Martínez-Martínez, Luis</creator><creator>Tomas, Maria</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200428</creationdate><title>In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens</title><author>Blasco, Lucia ; Ambroa, Anton ; Trastoy, Rocio ; Bleriot, Ines ; Moscoso, Miriam ; Fernández-Garcia, Laura ; Perez-Nadales, Elena ; Fernández-Cuenca, Felipe ; Torre-Cisneros, Julian ; Oteo-Iglesias, Jesus ; Oliver, Antonio ; Canton, Rafael ; Kidd, Tim ; Navarro, Ferran ; Miró, Elisenda ; Pascual, Alvaro ; Bou, German ; Martínez-Martínez, Luis ; Tomas, Maria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-2dac29f0970dd3c6786845ac7614289e0323d6f8350a44f7446db93f0543877f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/154</topic><topic>631/326</topic><topic>Antimicrobial activity</topic><topic>Antimicrobial agents</topic><topic>Bactericidal activity</topic><topic>Bronchopulmonary infection</topic><topic>Clinical isolates</topic><topic>Colistin</topic><topic>Colistin - pharmacology</topic><topic>Drug resistance</topic><topic>Drug Resistance, Multiple, Bacterial - drug effects</topic><topic>Endopeptidases - pharmacology</topic><topic>Genomes</topic><topic>Gram-Negative Bacteria - growth & development</topic><topic>Humanities and Social Sciences</topic><topic>Klebsiella pneumoniae</topic><topic>Microbial Sensitivity Tests</topic><topic>Minimum inhibitory concentration</topic><topic>multidisciplinary</topic><topic>Multidrug resistance</topic><topic>Phages</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Strains (organisms)</topic><topic>Turbidity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Blasco, Lucia</creatorcontrib><creatorcontrib>Ambroa, Anton</creatorcontrib><creatorcontrib>Trastoy, Rocio</creatorcontrib><creatorcontrib>Bleriot, Ines</creatorcontrib><creatorcontrib>Moscoso, Miriam</creatorcontrib><creatorcontrib>Fernández-Garcia, Laura</creatorcontrib><creatorcontrib>Perez-Nadales, Elena</creatorcontrib><creatorcontrib>Fernández-Cuenca, Felipe</creatorcontrib><creatorcontrib>Torre-Cisneros, Julian</creatorcontrib><creatorcontrib>Oteo-Iglesias, Jesus</creatorcontrib><creatorcontrib>Oliver, Antonio</creatorcontrib><creatorcontrib>Canton, Rafael</creatorcontrib><creatorcontrib>Kidd, Tim</creatorcontrib><creatorcontrib>Navarro, Ferran</creatorcontrib><creatorcontrib>Miró, Elisenda</creatorcontrib><creatorcontrib>Pascual, Alvaro</creatorcontrib><creatorcontrib>Bou, German</creatorcontrib><creatorcontrib>Martínez-Martínez, Luis</creatorcontrib><creatorcontrib>Tomas, Maria</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Blasco, Lucia</au><au>Ambroa, Anton</au><au>Trastoy, Rocio</au><au>Bleriot, Ines</au><au>Moscoso, Miriam</au><au>Fernández-Garcia, Laura</au><au>Perez-Nadales, Elena</au><au>Fernández-Cuenca, Felipe</au><au>Torre-Cisneros, Julian</au><au>Oteo-Iglesias, Jesus</au><au>Oliver, Antonio</au><au>Canton, Rafael</au><au>Kidd, Tim</au><au>Navarro, Ferran</au><au>Miró, Elisenda</au><au>Pascual, Alvaro</au><au>Bou, German</au><au>Martínez-Martínez, Luis</au><au>Tomas, Maria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-04-28</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>7163</spage><epage>7163</epage><pages>7163-7163</pages><artnum>7163</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates (
Acinetobacter baumannii
,
Pseudomonas aeruginosa
and
Klebsiella pneumoniae
) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of
A. baumannii
and
P. aeruginosa
tested and against 13 out of 17 strains of
K. pneumoniae
. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except
K. pneumoniae
. These results were confirmed
in vivo
in
G. mellonella
survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both
in vitro
and
in vivo
studies. This will potentially enable reduction of the dose of colistin used in clinical practice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32346029</pmid><doi>10.1038/s41598-020-64145-7</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 631/154 631/326 Antimicrobial activity Antimicrobial agents Bactericidal activity Bronchopulmonary infection Clinical isolates Colistin Colistin - pharmacology Drug resistance Drug Resistance, Multiple, Bacterial - drug effects Endopeptidases - pharmacology Genomes Gram-Negative Bacteria - growth & development Humanities and Social Sciences Klebsiella pneumoniae Microbial Sensitivity Tests Minimum inhibitory concentration multidisciplinary Multidrug resistance Phages Science Science (multidisciplinary) Strains (organisms) Turbidity |
| title | In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens |
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