A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics

Abstract β-lactam antibiotics, such as penicillin share a very unstable chemical structure. In water-based solutions, such as those used for clinical applications, the β-lactam ring is readily opened due to a nucleophilic or electrophilic attack, leading to the loss of antimicrobial activity. Since...

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Autores principales:	Belén Olivares, Fabián Martínez, Lina Rivas, Cristian Calderón, José M. Munita, Paola R. Campodonico
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Natural Deep Eutectic Solvents (NADES) Betaine Clavulanic Acid Nuclear Magnetic Resonance Spectroscopy McFarland Inoculum Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a7d505fc0ac42ab8e6ac7288c1ae786
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spelling	oai:doaj.org-article:8a7d505fc0ac42ab8e6ac7288c1ae7862021-12-02T15:08:27ZA Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics10.1038/s41598-018-33148-w2045-2322https://doaj.org/article/8a7d505fc0ac42ab8e6ac7288c1ae7862018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33148-whttps://doaj.org/toc/2045-2322Abstract β-lactam antibiotics, such as penicillin share a very unstable chemical structure. In water-based solutions, such as those used for clinical applications, the β-lactam ring is readily opened due to a nucleophilic or electrophilic attack, leading to the loss of antimicrobial activity. Since the achievement and maintenance of optimum therapeutic levels of β-lactam antibiotics is critical for the resolution of many infectious clinical situations, and to avoid antibiotic resistance generation, the design of new non-aqueous dosage forms is urgent. Recently, natural deep eutectic solvents (NADES) have emerged as alternative non-toxic and non-aqueous solvents for different biomedical applications. In this work, we formulated and characterized a NADES composed by betaine and urea (BU). Using this solvent, we evaluated the stability of clavulanic acid (CLV) and imipenem (IMP) and characterized their antimicrobial activities calculating the minimal inhibitory concentration. Characterization of BU solvent by infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that the obtained solvent has a microstructure mainly based on hydrogen bonding interactions and water addition strongly affects its dynamic. The stability of β-lactam antibiotic IMP and CLV using this solvent was increased by 7 fold and 2.5 fold respectively compared to water when analysed seven days after being dissolved. Microbiological assays showed that antibacterial activity at day seven was significantly decreased for both CLV and IMP when dissolved in water, while no change in their antibacterial properties was observed when antibiotics were dissolved in BU. The increased stability of IMP and CLV in BU may be related to the inert behaviour of the solvent and the higher dynamic restriction that helps antibiotics to maintain a more stable conformation. These data suggest the potential use of BU as a solvent to prevent degradation of β-lactam antibiotics.Belén OlivaresFabián MartínezLina RivasCristian CalderónJosé M. MunitaPaola R. CampodonicoNature PortfolioarticleNatural Deep Eutectic Solvents (NADES)BetaineClavulanic AcidNuclear Magnetic Resonance SpectroscopyMcFarland InoculumMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Natural Deep Eutectic Solvents (NADES) Betaine Clavulanic Acid Nuclear Magnetic Resonance Spectroscopy McFarland Inoculum Medicine R Science Q
spellingShingle	Natural Deep Eutectic Solvents (NADES) Betaine Clavulanic Acid Nuclear Magnetic Resonance Spectroscopy McFarland Inoculum Medicine R Science Q Belén Olivares Fabián Martínez Lina Rivas Cristian Calderón José M. Munita Paola R. Campodonico A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
description	Abstract β-lactam antibiotics, such as penicillin share a very unstable chemical structure. In water-based solutions, such as those used for clinical applications, the β-lactam ring is readily opened due to a nucleophilic or electrophilic attack, leading to the loss of antimicrobial activity. Since the achievement and maintenance of optimum therapeutic levels of β-lactam antibiotics is critical for the resolution of many infectious clinical situations, and to avoid antibiotic resistance generation, the design of new non-aqueous dosage forms is urgent. Recently, natural deep eutectic solvents (NADES) have emerged as alternative non-toxic and non-aqueous solvents for different biomedical applications. In this work, we formulated and characterized a NADES composed by betaine and urea (BU). Using this solvent, we evaluated the stability of clavulanic acid (CLV) and imipenem (IMP) and characterized their antimicrobial activities calculating the minimal inhibitory concentration. Characterization of BU solvent by infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that the obtained solvent has a microstructure mainly based on hydrogen bonding interactions and water addition strongly affects its dynamic. The stability of β-lactam antibiotic IMP and CLV using this solvent was increased by 7 fold and 2.5 fold respectively compared to water when analysed seven days after being dissolved. Microbiological assays showed that antibacterial activity at day seven was significantly decreased for both CLV and IMP when dissolved in water, while no change in their antibacterial properties was observed when antibiotics were dissolved in BU. The increased stability of IMP and CLV in BU may be related to the inert behaviour of the solvent and the higher dynamic restriction that helps antibiotics to maintain a more stable conformation. These data suggest the potential use of BU as a solvent to prevent degradation of β-lactam antibiotics.
format	article
author	Belén Olivares Fabián Martínez Lina Rivas Cristian Calderón José M. Munita Paola R. Campodonico
author_facet	Belén Olivares Fabián Martínez Lina Rivas Cristian Calderón José M. Munita Paola R. Campodonico
author_sort	Belén Olivares
title	A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
title_short	A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
title_full	A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
title_fullStr	A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
title_full_unstemmed	A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics
title_sort	natural deep eutectic solvent formulated to stabilize β-lactam antibiotics
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/8a7d505fc0ac42ab8e6ac7288c1ae786
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A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics

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