Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
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
_version_ 1782396879979413504
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
work_keys_str_mv AT gonzalespatrickr synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT peseskymitchellw synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT bouleyrenee synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT ballardanna synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT biddybrenta synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT suckowmarka synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT wolterwilliamr synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT schroedervaleriea synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT burnhamcareyannd synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT mobasheryshahriar synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT changmayland synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa
AT dantasgautam synergisticcollaterallysensitiveblactamcombinationssuppressresistanceinmrsa