Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.

The SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, has been shown to be associated with the emergence of resistance to antibiotics. Previously, we demonstrated that heterogeneous (HeR) MRSA strains, when exposed to sub-inhibitory concentrations of...

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Autores principales:	Konrad B Plata, Sarah Riosa, Christopher R Singh, Roberto R Rosato, Adriana E Rosato
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/737694b2f97549d9849a6d8c280f0948
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spelling	oai:doaj.org-article:737694b2f97549d9849a6d8c280f09482021-11-18T07:48:10ZTargeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.1932-620310.1371/journal.pone.0061083https://doaj.org/article/737694b2f97549d9849a6d8c280f09482013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637786/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, has been shown to be associated with the emergence of resistance to antibiotics. Previously, we demonstrated that heterogeneous (HeR) MRSA strains, when exposed to sub-inhibitory concentrations of oxacillin, were able to express a homogeneous high level of resistance (HoR). Moreover, we showed that oxacillin appeared to be the triggering factor of a β-lactam-mediated SOS response through lexA/recA regulators, responsible for an increased mutation rate and selection of a HoR derivative. In this work, we demonstrated, by selectively exposing to β-lactam and non-β-lactam cell wall inhibitors, that PBP1 plays a critical role in SOS-mediated recA activation and HeR-HoR selection. Functional analysis of PBP1 using an inducible PBP1-specific antisense construct showed that PBP1 depletion abolished both β-lactam-induced recA expression/activation and increased mutation rates during HeR/HoR selection. Furthermore, based on the observation that HeR/HoR selection is accompanied by compensatory increases in the expression of PBP1,-2, -2a, and -4, our study provides evidence that a combination of agents simultaneously targeting PBP1 and either PBP2 or PBP2a showed both in-vitro and in-vivo efficacy, thereby representing a therapeutic option for the treatment of highly resistant HoR-MRSA strains. The information gathered from these studies contributes to our understanding of β-lactam-mediated HeR/HoR selection and provides new insights, based on β-lactam synergistic combinations, that mitigate drug resistance for the treatment of MRSA infections.Konrad B PlataSarah RiosaChristopher R SinghRoberto R RosatoAdriana E RosatoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e61083 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Konrad B Plata Sarah Riosa Christopher R Singh Roberto R Rosato Adriana E Rosato Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
description	The SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, has been shown to be associated with the emergence of resistance to antibiotics. Previously, we demonstrated that heterogeneous (HeR) MRSA strains, when exposed to sub-inhibitory concentrations of oxacillin, were able to express a homogeneous high level of resistance (HoR). Moreover, we showed that oxacillin appeared to be the triggering factor of a β-lactam-mediated SOS response through lexA/recA regulators, responsible for an increased mutation rate and selection of a HoR derivative. In this work, we demonstrated, by selectively exposing to β-lactam and non-β-lactam cell wall inhibitors, that PBP1 plays a critical role in SOS-mediated recA activation and HeR-HoR selection. Functional analysis of PBP1 using an inducible PBP1-specific antisense construct showed that PBP1 depletion abolished both β-lactam-induced recA expression/activation and increased mutation rates during HeR/HoR selection. Furthermore, based on the observation that HeR/HoR selection is accompanied by compensatory increases in the expression of PBP1,-2, -2a, and -4, our study provides evidence that a combination of agents simultaneously targeting PBP1 and either PBP2 or PBP2a showed both in-vitro and in-vivo efficacy, thereby representing a therapeutic option for the treatment of highly resistant HoR-MRSA strains. The information gathered from these studies contributes to our understanding of β-lactam-mediated HeR/HoR selection and provides new insights, based on β-lactam synergistic combinations, that mitigate drug resistance for the treatment of MRSA infections.
format	article
author	Konrad B Plata Sarah Riosa Christopher R Singh Roberto R Rosato Adriana E Rosato
author_facet	Konrad B Plata Sarah Riosa Christopher R Singh Roberto R Rosato Adriana E Rosato
author_sort	Konrad B Plata
title	Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
title_short	Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
title_full	Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
title_fullStr	Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
title_full_unstemmed	Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
title_sort	targeting of pbp1 by β-lactams determines reca/sos response activation in heterogeneous mrsa clinical strains.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/737694b2f97549d9849a6d8c280f0948
work_keys_str_mv	AT konradbplata targetingofpbp1byblactamsdeterminesrecasosresponseactivationinheterogeneousmrsaclinicalstrains AT sarahriosa targetingofpbp1byblactamsdeterminesrecasosresponseactivationinheterogeneousmrsaclinicalstrains AT christopherrsingh targetingofpbp1byblactamsdeterminesrecasosresponseactivationinheterogeneousmrsaclinicalstrains AT robertorrosato targetingofpbp1byblactamsdeterminesrecasosresponseactivationinheterogeneousmrsaclinicalstrains AT adrianaerosato targetingofpbp1byblactamsdeterminesrecasosresponseactivationinheterogeneousmrsaclinicalstrains
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Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.

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