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Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

[Image: see text] Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure–activity relationship u...

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Autores principales: Wesseling, Charlotte M. J., Slingerland, Cornelis J., Veraar, Shanice, Lok, Samantha, Martin, Nathaniel I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669655/
https://www.ncbi.nlm.nih.gov/pubmed/34766746
http://dx.doi.org/10.1021/acsinfecdis.1c00466
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author Wesseling, Charlotte M. J.
Slingerland, Cornelis J.
Veraar, Shanice
Lok, Samantha
Martin, Nathaniel I.
author_facet Wesseling, Charlotte M. J.
Slingerland, Cornelis J.
Veraar, Shanice
Lok, Samantha
Martin, Nathaniel I.
author_sort Wesseling, Charlotte M. J.
collection PubMed
description [Image: see text] Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure–activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
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spelling pubmed-86696552021-12-14 Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens Wesseling, Charlotte M. J. Slingerland, Cornelis J. Veraar, Shanice Lok, Samantha Martin, Nathaniel I. ACS Infect Dis [Image: see text] Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure–activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains. American Chemical Society 2021-11-12 2021-12-10 /pmc/articles/PMC8669655/ /pubmed/34766746 http://dx.doi.org/10.1021/acsinfecdis.1c00466 Text en © 2021 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Wesseling, Charlotte M. J.
Slingerland, Cornelis J.
Veraar, Shanice
Lok, Samantha
Martin, Nathaniel I.
Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title_full Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title_fullStr Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title_full_unstemmed Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title_short Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
title_sort structure–activity studies with bis-amidines that potentiate gram-positive specific antibiotics against gram-negative pathogens
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669655/
https://www.ncbi.nlm.nih.gov/pubmed/34766746
http://dx.doi.org/10.1021/acsinfecdis.1c00466
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