Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784614823219167232 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8669655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wesselingcharlottemj structureactivitystudieswithbisamidinesthatpotentiategrampositivespecificantibioticsagainstgramnegativepathogens AT slingerlandcornelisj structureactivitystudieswithbisamidinesthatpotentiategrampositivespecificantibioticsagainstgramnegativepathogens AT veraarshanice structureactivitystudieswithbisamidinesthatpotentiategrampositivespecificantibioticsagainstgramnegativepathogens AT loksamantha structureactivitystudieswithbisamidinesthatpotentiategrampositivespecificantibioticsagainstgramnegativepathogens AT martinnathanieli structureactivitystudieswithbisamidinesthatpotentiategrampositivespecificantibioticsagainstgramnegativepathogens |