Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>

ABSTRACT Penicillin-binding proteins (PBPs) are essential for bacterial cell wall biosynthesis, and several are clinically validated antibacterial targets of β-lactam antibiotics. We identified mutations in the mrdA gene encoding the PBP2 protein in two Escherichia coli blaNDM-1 clinical isolates th...

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Autores principales:	Srijan Ranjitkar, Folkert Reck, Xiaobo Ke, Qingming Zhu, Glenn McEnroe, Sara L. Lopez, Charles R. Dean
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	NDM-1 carbapenems diazabicyclooctane penicillin-binding proteins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3c130500a04c493ebeeaca6cf0d68b31
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spelling	oai:doaj.org-article:3c130500a04c493ebeeaca6cf0d68b312021-11-15T15:22:27ZIdentification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>10.1128/mSphere.00074-192379-5042https://doaj.org/article/3c130500a04c493ebeeaca6cf0d68b312019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00074-19https://doaj.org/toc/2379-5042ABSTRACT Penicillin-binding proteins (PBPs) are essential for bacterial cell wall biosynthesis, and several are clinically validated antibacterial targets of β-lactam antibiotics. We identified mutations in the mrdA gene encoding the PBP2 protein in two Escherichia coli blaNDM-1 clinical isolates that reduce susceptibility to carbapenems and to the intrinsic antibacterial activity of a diazabicyclooctane (DBO) PBP2 and β-lactamase inhibitor. These mutations coexisted with previously described mutations in ftsI (encoding PBP3) that reduce susceptibility to monobactams, penicillins, and cephalosporins. Clinical exposure to β-lactams is driving the emergence of multifactorial resistance that may impact the therapeutic usefulness of existing antibacterials and novel compounds that target PBPs. IMPORTANCE Emerging antibacterial resistance is a consequence of the continued use of our current antibacterial therapies, and it is limiting their utility, especially for infections caused by multidrug-resistant isolates. β-Lactams have enjoyed extensive clinical success, but their broad usage is linked to perhaps the most extensive and progressive example of resistance development for any antibacterial scaffold. In Gram-negative pathogens, this largely involves constant evolution of new β-lactamases able to degrade successive generations of this scaffold. In addition, more recently, alterations in the targets of these compounds, penicillin-binding proteins (PBPs), are being described in clinical isolates, which often also have multiple β-lactamases. This study underscores the multifactorial nature of β-lactam resistance by uncovering alterations of PBP2 that reduce susceptibility to carbapenems in E. coli clinical isolates that also have alterations of PBP3 and express the NDM-1 β-lactamase. The changes in PBP2 also reduced susceptibility to the intrinsic antibacterial activity of some diazabicyclooctane (DBO) compounds that can target PBP2. This may have implications for the development and use of the members of this relatively newer scaffold that are inhibitors of PBP2 in addition to their inhibition of serine-β-lactamases.Srijan RanjitkarFolkert ReckXiaobo KeQingming ZhuGlenn McEnroeSara L. LopezCharles R. DeanAmerican Society for MicrobiologyarticleNDM-1carbapenemsdiazabicyclooctanepenicillin-binding proteinsMicrobiologyQR1-502ENmSphere, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	NDM-1 carbapenems diazabicyclooctane penicillin-binding proteins Microbiology QR1-502
spellingShingle	NDM-1 carbapenems diazabicyclooctane penicillin-binding proteins Microbiology QR1-502 Srijan Ranjitkar Folkert Reck Xiaobo Ke Qingming Zhu Glenn McEnroe Sara L. Lopez Charles R. Dean Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
description	ABSTRACT Penicillin-binding proteins (PBPs) are essential for bacterial cell wall biosynthesis, and several are clinically validated antibacterial targets of β-lactam antibiotics. We identified mutations in the mrdA gene encoding the PBP2 protein in two Escherichia coli blaNDM-1 clinical isolates that reduce susceptibility to carbapenems and to the intrinsic antibacterial activity of a diazabicyclooctane (DBO) PBP2 and β-lactamase inhibitor. These mutations coexisted with previously described mutations in ftsI (encoding PBP3) that reduce susceptibility to monobactams, penicillins, and cephalosporins. Clinical exposure to β-lactams is driving the emergence of multifactorial resistance that may impact the therapeutic usefulness of existing antibacterials and novel compounds that target PBPs. IMPORTANCE Emerging antibacterial resistance is a consequence of the continued use of our current antibacterial therapies, and it is limiting their utility, especially for infections caused by multidrug-resistant isolates. β-Lactams have enjoyed extensive clinical success, but their broad usage is linked to perhaps the most extensive and progressive example of resistance development for any antibacterial scaffold. In Gram-negative pathogens, this largely involves constant evolution of new β-lactamases able to degrade successive generations of this scaffold. In addition, more recently, alterations in the targets of these compounds, penicillin-binding proteins (PBPs), are being described in clinical isolates, which often also have multiple β-lactamases. This study underscores the multifactorial nature of β-lactam resistance by uncovering alterations of PBP2 that reduce susceptibility to carbapenems in E. coli clinical isolates that also have alterations of PBP3 and express the NDM-1 β-lactamase. The changes in PBP2 also reduced susceptibility to the intrinsic antibacterial activity of some diazabicyclooctane (DBO) compounds that can target PBP2. This may have implications for the development and use of the members of this relatively newer scaffold that are inhibitors of PBP2 in addition to their inhibition of serine-β-lactamases.
format	article
author	Srijan Ranjitkar Folkert Reck Xiaobo Ke Qingming Zhu Glenn McEnroe Sara L. Lopez Charles R. Dean
author_facet	Srijan Ranjitkar Folkert Reck Xiaobo Ke Qingming Zhu Glenn McEnroe Sara L. Lopez Charles R. Dean
author_sort	Srijan Ranjitkar
title	Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
title_short	Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
title_full	Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
title_fullStr	Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
title_full_unstemmed	Identification of Mutations in the <italic toggle="yes">mrdA</italic> Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of <named-content content-type="genus-species">Escherichia coli</named-content> Clinical Isolates with Mutations in <italic toggle="yes">ftsI</italic> (PBP3) and Which Carry <italic toggle="yes">bla</italic><sub>NDM-1</sub>
title_sort	identification of mutations in the <italic toggle="yes">mrda</italic> gene encoding pbp2 that reduce carbapenem and diazabicyclooctane susceptibility of <named-content content-type="genus-species">escherichia coli</named-content> clinical isolates with mutations in <italic toggle="yes">ftsi</italic> (pbp3) and which carry <italic toggle="yes">bla</italic><sub>ndm-1</sub>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/3c130500a04c493ebeeaca6cf0d68b31
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