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In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
Mario Juhas,
Emma Widlake,
Jeanette Teo,
Douglas L Huseby,
Jon Tyrrell 
,
Yury S Polikanov,
Onur Ercan,
Anna Petersson,
Sha Cao,
Ali F Aboklaish,
Anna Rominski,
David Crich,
Erik C Böttger,
Timothy R Walsh,
Diarmaid Hughes ,
Sven N Hobbie
,
Yury S Polikanov,
Onur Ercan,
Anna Petersson,
Sha Cao,
Ali F Aboklaish,
Anna Rominski,
David Crich,
Erik C Böttger,
Timothy R Walsh,
Diarmaid Hughes ,
Sven N Hobbie
Journal of Antimicrobial Chemotherapy, Volume: 74, Issue: 4, Pages: 944 - 952
Swansea University Author:
Jon Tyrrell
-
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Copyright: The Author(s) 2019. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.
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DOI (Published version): 10.1093/jac/dky546
Abstract
ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almo...
| Published in: | Journal of Antimicrobial Chemotherapy |
|---|---|
| ISSN: | 0305-7453 1460-2091 |
| Published: |
Oxford University Press (OUP)
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70435 |
| first_indexed |
2025-09-21T22:01:41Z |
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| last_indexed |
2025-10-14T10:07:06Z |
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cronfa70435 |
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SURis |
| fullrecord |
<?xml version="1.0"?><rfc1807><datestamp>2025-10-13T15:36:34.5759065</datestamp><bib-version>v2</bib-version><id>70435</id><entry>2025-09-21</entry><title>In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii</title><swanseaauthors><author><sid>ad510c73555adf718387af219e235a6e</sid><ORCID>0000-0001-8565-2590</ORCID><firstname>Jon</firstname><surname>Tyrrell</surname><name>Jon Tyrrell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-09-21</date><deptcode>MEDS</deptcode><abstract>ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.MethodsA thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.ResultsMIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.ConclusionsIts superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.</abstract><type>Journal Article</type><journal>Journal of Antimicrobial Chemotherapy</journal><volume>74</volume><journalNumber>4</journalNumber><paginationStart>944</paginationStart><paginationEnd>952</paginationEnd><publisher>Oxford University Press (OUP)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0305-7453</issnPrint><issnElectronic>1460-2091</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-04-01</publishedDate><doi>10.1093/jac/dky546</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium (www.nd4bb-enable.eu) and has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n115583, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/20072013) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in kind contribution. The ENABLE project is also financially supported by contributions from Academic and Small and medium-sized enterprise (SME) partners.</funders><projectreference/><lastEdited>2025-10-13T15:36:34.5759065</lastEdited><Created>2025-09-21T18:17:29.4701322</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Mario</firstname><surname>Juhas</surname><order>1</order></author><author><firstname>Emma</firstname><surname>Widlake</surname><order>2</order></author><author><firstname>Jeanette</firstname><surname>Teo</surname><order>3</order></author><author><firstname>Douglas L</firstname><surname>Huseby</surname><order>4</order></author><author><firstname>Jon</firstname><surname>Tyrrell</surname><orcid>0000-0001-8565-2590</orcid><order>5</order></author><author><firstname>Yury S</firstname><surname>Polikanov</surname><order>6</order></author><author><firstname>Onur</firstname><surname>Ercan</surname><order>7</order></author><author><firstname>Anna</firstname><surname>Petersson</surname><order>8</order></author><author><firstname>Sha</firstname><surname>Cao</surname><order>9</order></author><author><firstname>Ali F</firstname><surname>Aboklaish</surname><order>10</order></author><author><firstname>Anna</firstname><surname>Rominski</surname><order>11</order></author><author><firstname>David</firstname><surname>Crich</surname><order>12</order></author><author><firstname>Erik C</firstname><surname>Böttger</surname><order>13</order></author><author><firstname>Timothy R</firstname><surname>Walsh</surname><order>14</order></author><author><firstname>Diarmaid</firstname><surname>Hughes</surname><orcid>0000-0002-7456-9182</orcid><order>15</order></author><author><firstname>Sven N</firstname><surname>Hobbie</surname><order>16</order></author></authors><documents><document><filename>70435__35327__1781d13329264c60b7c36ea67914b5d3.pdf</filename><originalFilename>70435.VoR.pdf</originalFilename><uploaded>2025-10-13T15:34:22.9688767</uploaded><type>Output</type><contentLength>664629</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright: The Author(s) 2019. 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2025-10-13T15:36:34.5759065 v2 70435 2025-09-21 In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii ad510c73555adf718387af219e235a6e 0000-0001-8565-2590 Jon Tyrrell Jon Tyrrell true false 2025-09-21 MEDS ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.MethodsA thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.ResultsMIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.ConclusionsIts superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics. Journal Article Journal of Antimicrobial Chemotherapy 74 4 944 952 Oxford University Press (OUP) 0305-7453 1460-2091 1 4 2019 2019-04-01 10.1093/jac/dky546 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium (www.nd4bb-enable.eu) and has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n115583, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/20072013) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in kind contribution. The ENABLE project is also financially supported by contributions from Academic and Small and medium-sized enterprise (SME) partners. 2025-10-13T15:36:34.5759065 2025-09-21T18:17:29.4701322 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Mario Juhas 1 Emma Widlake 2 Jeanette Teo 3 Douglas L Huseby 4 Jon Tyrrell 0000-0001-8565-2590 5 Yury S Polikanov 6 Onur Ercan 7 Anna Petersson 8 Sha Cao 9 Ali F Aboklaish 10 Anna Rominski 11 David Crich 12 Erik C Böttger 13 Timothy R Walsh 14 Diarmaid Hughes 0000-0002-7456-9182 15 Sven N Hobbie 16 70435__35327__1781d13329264c60b7c36ea67914b5d3.pdf 70435.VoR.pdf 2025-10-13T15:34:22.9688767 Output 664629 application/pdf Version of Record true Copyright: The Author(s) 2019. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License. true eng http://creativecommons.org/licenses/by-nc/4.0/ |
| title |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
| spellingShingle |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii Jon Tyrrell |
| title_short |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
| title_full |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
| title_fullStr |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
| title_full_unstemmed |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
| title_sort |
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii |
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ad510c73555adf718387af219e235a6e |
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ad510c73555adf718387af219e235a6e_***_Jon Tyrrell |
| author |
Jon Tyrrell |
| author2 |
Mario Juhas Emma Widlake Jeanette Teo Douglas L Huseby Jon Tyrrell Yury S Polikanov Onur Ercan Anna Petersson Sha Cao Ali F Aboklaish Anna Rominski David Crich Erik C Böttger Timothy R Walsh Diarmaid Hughes Sven N Hobbie |
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Journal article |
| container_title |
Journal of Antimicrobial Chemotherapy |
| container_volume |
74 |
| container_issue |
4 |
| container_start_page |
944 |
| publishDate |
2019 |
| institution |
Swansea University |
| issn |
0305-7453 1460-2091 |
| doi_str_mv |
10.1093/jac/dky546 |
| publisher |
Oxford University Press (OUP) |
| college_str |
Faculty of Medicine, Health and Life Sciences |
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|
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facultyofmedicinehealthandlifesciences |
| hierarchy_top_title |
Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
| hierarchy_parent_title |
Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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| description |
ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.MethodsA thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.ResultsMIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.ConclusionsIts superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics. |
| published_date |
2019-04-01T05:26:08Z |
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11.089572 |