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Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem/piperacillin/tazobactam (ME/PI/TZ) acts synergisti...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618095/ https://www.ncbi.nlm.nih.gov/pubmed/26368589 http://dx.doi.org/10.1038/nchembio.1911 |
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author | Gonzales, Patrick R. Pesesky, Mitchell W. Bouley, Renee Ballard, Anna Biddy, Brent A. Suckow, Mark A. Wolter, William R. Schroeder, Valerie A. Burnham, Carey-Ann D. Mobashery, Shahriar Chang, Mayland Dantas, Gautam |
author_facet | Gonzales, Patrick R. Pesesky, Mitchell W. Bouley, Renee Ballard, Anna Biddy, Brent A. Suckow, Mark A. Wolter, William R. Schroeder, Valerie A. Burnham, Carey-Ann D. Mobashery, Shahriar Chang, Mayland Dantas, Gautam |
author_sort | Gonzales, Patrick R. |
collection | PubMed |
description | Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem/piperacillin/tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA N315 and 72 clinical MRSA isolates in vitro, and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem/penicillin/β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein 2a (PBP2a) action via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing similar in vivo activity to linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans. |
format | Online Article Text |
id | pubmed-4618095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-46180952016-05-01 Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA Gonzales, Patrick R. Pesesky, Mitchell W. Bouley, Renee Ballard, Anna Biddy, Brent A. Suckow, Mark A. Wolter, William R. Schroeder, Valerie A. Burnham, Carey-Ann D. Mobashery, Shahriar Chang, Mayland Dantas, Gautam Nat Chem Biol Article Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem/piperacillin/tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA N315 and 72 clinical MRSA isolates in vitro, and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem/penicillin/β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein 2a (PBP2a) action via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing similar in vivo activity to linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans. 2015-09-14 2015-11 /pmc/articles/PMC4618095/ /pubmed/26368589 http://dx.doi.org/10.1038/nchembio.1911 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Gonzales, Patrick R. Pesesky, Mitchell W. Bouley, Renee Ballard, Anna Biddy, Brent A. Suckow, Mark A. Wolter, William R. Schroeder, Valerie A. Burnham, Carey-Ann D. Mobashery, Shahriar Chang, Mayland Dantas, Gautam Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title | Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title_full | Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title_fullStr | Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title_full_unstemmed | Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title_short | Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA |
title_sort | synergistic, collaterally sensitive β-lactam combinations suppress resistance in mrsa |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618095/ https://www.ncbi.nlm.nih.gov/pubmed/26368589 http://dx.doi.org/10.1038/nchembio.1911 |
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