Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria
Abstract A main challenge in chemotherapy is to determine the in cellulo parameters modulating the drug concentration required for therapeutic action. It is absolutely urgent to understand membrane permeation and intracellular concentration of antibiotics in clinical isolates: passing the membrane b...
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Nature Portfolio
2017
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oai:doaj.org-article:ca80691df79d435fac589a85f21b09202021-12-02T16:08:12ZMicrospectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria10.1038/s41598-017-00945-82045-2322https://doaj.org/article/ca80691df79d435fac589a85f21b09202017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00945-8https://doaj.org/toc/2045-2322Abstract A main challenge in chemotherapy is to determine the in cellulo parameters modulating the drug concentration required for therapeutic action. It is absolutely urgent to understand membrane permeation and intracellular concentration of antibiotics in clinical isolates: passing the membrane barrier to reach the threshold concentration inside the bacterial periplasm or cytoplasm is the pivotal step of antibacterial activity. Ceftazidime (CAZ) is a key molecule of the combination therapy for treating resistant bacteria. We designed and synthesized different fluorescent CAZ derivatives (CAZ*, CAZ**) to dissect the early step of translocation-accumulation across bacterial membrane. Their activities were determined on E. coli strains and on selected clinical isolates overexpressing ß-lactamases. The accumulation of CAZ* and CAZ** were determined by microspectrofluorimetry and epifluorimetry. The derivatives were properly translocated to the periplasmic space when we permeabilize the outer membrane barrier. The periplasmic location of CAZ** was related to a significant antibacterial activity and with the outer membrane permeability. This study demonstrated the correlation between periplasmic accumulation and antibiotic activity. We also validated the method for approaching ß-lactam permeation relative to membrane permeability and paved the way for an original matrix for determining “Structure Intracellular Accumulation Activity Relationship” for the development of new therapeutic candidates.Anas AllamLaure MaigreJulia VergalliEstelle DumontBertrand CinquinRodolphe Alves de SousaJelena PajovicElizabeth PinetNikaia SmithJean-Philippe HerbeuvalMatthieu RéfrégiersIsabelle ArtaudJean-Marie PagèsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
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Medicine R Science Q Anas Allam Laure Maigre Julia Vergalli Estelle Dumont Bertrand Cinquin Rodolphe Alves de Sousa Jelena Pajovic Elizabeth Pinet Nikaia Smith Jean-Philippe Herbeuval Matthieu Réfrégiers Isabelle Artaud Jean-Marie Pagès Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| description |
Abstract A main challenge in chemotherapy is to determine the in cellulo parameters modulating the drug concentration required for therapeutic action. It is absolutely urgent to understand membrane permeation and intracellular concentration of antibiotics in clinical isolates: passing the membrane barrier to reach the threshold concentration inside the bacterial periplasm or cytoplasm is the pivotal step of antibacterial activity. Ceftazidime (CAZ) is a key molecule of the combination therapy for treating resistant bacteria. We designed and synthesized different fluorescent CAZ derivatives (CAZ*, CAZ**) to dissect the early step of translocation-accumulation across bacterial membrane. Their activities were determined on E. coli strains and on selected clinical isolates overexpressing ß-lactamases. The accumulation of CAZ* and CAZ** were determined by microspectrofluorimetry and epifluorimetry. The derivatives were properly translocated to the periplasmic space when we permeabilize the outer membrane barrier. The periplasmic location of CAZ** was related to a significant antibacterial activity and with the outer membrane permeability. This study demonstrated the correlation between periplasmic accumulation and antibiotic activity. We also validated the method for approaching ß-lactam permeation relative to membrane permeability and paved the way for an original matrix for determining “Structure Intracellular Accumulation Activity Relationship” for the development of new therapeutic candidates. |
| format |
article |
| author |
Anas Allam Laure Maigre Julia Vergalli Estelle Dumont Bertrand Cinquin Rodolphe Alves de Sousa Jelena Pajovic Elizabeth Pinet Nikaia Smith Jean-Philippe Herbeuval Matthieu Réfrégiers Isabelle Artaud Jean-Marie Pagès |
| author_facet |
Anas Allam Laure Maigre Julia Vergalli Estelle Dumont Bertrand Cinquin Rodolphe Alves de Sousa Jelena Pajovic Elizabeth Pinet Nikaia Smith Jean-Philippe Herbeuval Matthieu Réfrégiers Isabelle Artaud Jean-Marie Pagès |
| author_sort |
Anas Allam |
| title |
Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| title_short |
Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| title_full |
Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| title_fullStr |
Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| title_full_unstemmed |
Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria |
| title_sort |
microspectrofluorimetry to dissect the permeation of ceftazidime in gram-negative bacteria |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/ca80691df79d435fac589a85f21b0920 |
| work_keys_str_mv |
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1718384621112000512 |