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In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
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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 |
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| ISSN: | 0305-7453 1460-2091 |
| Published: |
Oxford University Press (OUP)
2019
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70435 |
| 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| 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. |
| Issue: |
4 |
| Start Page: |
944 |
| End Page: |
952 |