Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases

ABSTRACT In recent decades, carbapenems have been considered the last line of antibiotic therapy for Gram-negative bacterial infections. Unfortunately, strains carrying a high diversity of β-lactamases able to hydrolyze carbapenems have emerged in the clinical setting. Among them, VIM β-lactamases h...

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Autores principales:	Laura Martínez-García, José M. González-Alba, Fernando Baquero, Rafael Cantón, Juan Carlos Galán
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	VIM ceftazidime diversification evolution phylogeny Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c7e98d1d9a1843aa9ae8c889bf5f9b2d
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spelling	oai:doaj.org-article:c7e98d1d9a1843aa9ae8c889bf5f9b2d2021-11-15T16:00:26ZCeftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases10.1128/mBio.02109-172150-7511https://doaj.org/article/c7e98d1d9a1843aa9ae8c889bf5f9b2d2018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02109-17https://doaj.org/toc/2150-7511ABSTRACT In recent decades, carbapenems have been considered the last line of antibiotic therapy for Gram-negative bacterial infections. Unfortunately, strains carrying a high diversity of β-lactamases able to hydrolyze carbapenems have emerged in the clinical setting. Among them, VIM β-lactamases have diversified in a bloom of variants. The evolutionary reconstructions performed in this work revealed that, at the end of the 1980s, two independent events involving diversification from VIM-2 and VIM-4 produced at least 25 VIM variants. Later, a third event involving diversification from VIM-1 occurred in the mid-1990s. In a second approach to understanding the emergence of VIM carbapenemases, 44 mutants derived from VIM-2 and VIM-4 were obtained by site-directed mutagenesis based on those positions predicted to be under positive selection. These variants were expressed in an isogenic context. The more-evolved variants yielded increased levels of hydrolytic efficiency toward ceftazidime to a higher degree than toward carbapenems. In fact, an antagonist effect was frequently observed. These results led us to develop an experimental-evolution step. When Escherichia coli strains carrying VIM-2 or VIM-4 were submitted to serial passages at increasing concentrations of carbapenems or ceftazidime, more-efficient new variants (such as VIM-11 and VIM-1, with N165S [bearing a change from N to S at position 165] and R228S mutations, respectively) were only obtained when ceftazidime was present. Therefore, the observed effect of ceftazidime in the diversification and selection of VIM variants might help to explain the recent bloom of carbapenemase diversity, and it also represents another example of the potential universal effect exerted by ceftazidime in the selection of more-efficient β-lactamase variants, as in TEM, CTX-M, or KPC enzymes. IMPORTANCE One of the objectives recently proposed by the World Health Organization (WHO) Assembly in the global plan on antimicrobial resistance was to improve the understanding and knowledge of antimicrobial resistance. In the present work, we paid attention to the drivers of diversification and selection of new carbapenemases in Gram-negative bacteria, which occupy one of the most critical places in the WHO priority list of antibiotic-resistant microorganisms. Based on evolutionary-reconstruction, site-directed-mutagenesis, and experimental-evolution approaches, we proposed a critical role of ceftazidime exposure in the selection of VIM carbapenemase variants. This surprising finding is also applicable to other β-lactamases, indicating that ceftazidime, and not other antibiotics, might have a universal effect in the diversification of β-lactamases. Our results might help to define future strategies to reconsider the extended use of ceftazidime.Laura Martínez-GarcíaJosé M. González-AlbaFernando BaqueroRafael CantónJuan Carlos GalánAmerican Society for MicrobiologyarticleVIMceftazidimediversificationevolutionphylogenyMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	VIM ceftazidime diversification evolution phylogeny Microbiology QR1-502
spellingShingle	VIM ceftazidime diversification evolution phylogeny Microbiology QR1-502 Laura Martínez-García José M. González-Alba Fernando Baquero Rafael Cantón Juan Carlos Galán Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
description	ABSTRACT In recent decades, carbapenems have been considered the last line of antibiotic therapy for Gram-negative bacterial infections. Unfortunately, strains carrying a high diversity of β-lactamases able to hydrolyze carbapenems have emerged in the clinical setting. Among them, VIM β-lactamases have diversified in a bloom of variants. The evolutionary reconstructions performed in this work revealed that, at the end of the 1980s, two independent events involving diversification from VIM-2 and VIM-4 produced at least 25 VIM variants. Later, a third event involving diversification from VIM-1 occurred in the mid-1990s. In a second approach to understanding the emergence of VIM carbapenemases, 44 mutants derived from VIM-2 and VIM-4 were obtained by site-directed mutagenesis based on those positions predicted to be under positive selection. These variants were expressed in an isogenic context. The more-evolved variants yielded increased levels of hydrolytic efficiency toward ceftazidime to a higher degree than toward carbapenems. In fact, an antagonist effect was frequently observed. These results led us to develop an experimental-evolution step. When Escherichia coli strains carrying VIM-2 or VIM-4 were submitted to serial passages at increasing concentrations of carbapenems or ceftazidime, more-efficient new variants (such as VIM-11 and VIM-1, with N165S [bearing a change from N to S at position 165] and R228S mutations, respectively) were only obtained when ceftazidime was present. Therefore, the observed effect of ceftazidime in the diversification and selection of VIM variants might help to explain the recent bloom of carbapenemase diversity, and it also represents another example of the potential universal effect exerted by ceftazidime in the selection of more-efficient β-lactamase variants, as in TEM, CTX-M, or KPC enzymes. IMPORTANCE One of the objectives recently proposed by the World Health Organization (WHO) Assembly in the global plan on antimicrobial resistance was to improve the understanding and knowledge of antimicrobial resistance. In the present work, we paid attention to the drivers of diversification and selection of new carbapenemases in Gram-negative bacteria, which occupy one of the most critical places in the WHO priority list of antibiotic-resistant microorganisms. Based on evolutionary-reconstruction, site-directed-mutagenesis, and experimental-evolution approaches, we proposed a critical role of ceftazidime exposure in the selection of VIM carbapenemase variants. This surprising finding is also applicable to other β-lactamases, indicating that ceftazidime, and not other antibiotics, might have a universal effect in the diversification of β-lactamases. Our results might help to define future strategies to reconsider the extended use of ceftazidime.
format	article
author	Laura Martínez-García José M. González-Alba Fernando Baquero Rafael Cantón Juan Carlos Galán
author_facet	Laura Martínez-García José M. González-Alba Fernando Baquero Rafael Cantón Juan Carlos Galán
author_sort	Laura Martínez-García
title	Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
title_short	Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
title_full	Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
title_fullStr	Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
title_full_unstemmed	Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases
title_sort	ceftazidime is the key diversification and selection driver of vim-type carbapenemases
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c7e98d1d9a1843aa9ae8c889bf5f9b2d
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Ceftazidime Is the Key Diversification and Selection Driver of VIM-Type Carbapenemases

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