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Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers

Lariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often...

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Autores principales: Patel, Mohit B., Spikes, Helena, Bailey, Robert S., Connell, Thomas, Gill, Hannah, Gokel, Michael R., Harris, Rebecca, Meisel, Joseph W., Negin, Saeedeh, Yin, Shanheng Andrew, Gokel, George W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603992/
https://www.ncbi.nlm.nih.gov/pubmed/37887214
http://dx.doi.org/10.3390/antibiotics12101513
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author Patel, Mohit B.
Spikes, Helena
Bailey, Robert S.
Connell, Thomas
Gill, Hannah
Gokel, Michael R.
Harris, Rebecca
Meisel, Joseph W.
Negin, Saeedeh
Yin, Shanheng Andrew
Gokel, George W.
author_facet Patel, Mohit B.
Spikes, Helena
Bailey, Robert S.
Connell, Thomas
Gill, Hannah
Gokel, Michael R.
Harris, Rebecca
Meisel, Joseph W.
Negin, Saeedeh
Yin, Shanheng Andrew
Gokel, George W.
author_sort Patel, Mohit B.
collection PubMed
description Lariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.
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spelling pubmed-106039922023-10-28 Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers Patel, Mohit B. Spikes, Helena Bailey, Robert S. Connell, Thomas Gill, Hannah Gokel, Michael R. Harris, Rebecca Meisel, Joseph W. Negin, Saeedeh Yin, Shanheng Andrew Gokel, George W. Antibiotics (Basel) Article Lariat ethers are macrocyclic polyethers—crown ethers—to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter’s potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development. MDPI 2023-10-05 /pmc/articles/PMC10603992/ /pubmed/37887214 http://dx.doi.org/10.3390/antibiotics12101513 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Patel, Mohit B.
Spikes, Helena
Bailey, Robert S.
Connell, Thomas
Gill, Hannah
Gokel, Michael R.
Harris, Rebecca
Meisel, Joseph W.
Negin, Saeedeh
Yin, Shanheng Andrew
Gokel, George W.
Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title_full Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title_fullStr Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title_full_unstemmed Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title_short Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers
title_sort antimicrobial and adjuvant potencies of di-n-alkyl substituted diazalariat ethers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603992/
https://www.ncbi.nlm.nih.gov/pubmed/37887214
http://dx.doi.org/10.3390/antibiotics12101513
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