From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump

Stefano Sabatini, Glenn W. Kaatz, Gian Maria Rossolini, David Brandini, Arnaldo Fravolini

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.

Original languageEnglish
Pages (from-to)4321-4330
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
DOIs
Publication statusPublished - Jul 24 2008

Fingerprint

Staphylococcus aureus
Pumps
Ciprofloxacin
Derivatives
Ethidium
Fluoroquinolones
Anti-Infective Agents
Bacteria
Phenotype
Assays
1,4-benzothiazine
phenothiazine
Substrates

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. / Sabatini, Stefano; Kaatz, Glenn W.; Rossolini, Gian Maria; Brandini, David; Fravolini, Arnaldo.

In: Journal of Medicinal Chemistry, Vol. 51, No. 14, 24.07.2008, p. 4321-4330.

Research output: Contribution to journalArticle

Sabatini, Stefano ; Kaatz, Glenn W. ; Rossolini, Gian Maria ; Brandini, David ; Fravolini, Arnaldo. / From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 14. pp. 4321-4330.
@article{9796843ece46459496bc23b5ca0d3c82,
title = "From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump",
abstract = "Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.",
author = "Stefano Sabatini and Kaatz, {Glenn W.} and Rossolini, {Gian Maria} and David Brandini and Arnaldo Fravolini",
year = "2008",
month = "7",
day = "24",
doi = "10.1021/jm701623q",
language = "English",
volume = "51",
pages = "4321--4330",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump

AU - Sabatini, Stefano

AU - Kaatz, Glenn W.

AU - Rossolini, Gian Maria

AU - Brandini, David

AU - Fravolini, Arnaldo

PY - 2008/7/24

Y1 - 2008/7/24

N2 - Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.

AB - Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.

UR - http://www.scopus.com/inward/record.url?scp=47749084644&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=47749084644&partnerID=8YFLogxK

U2 - 10.1021/jm701623q

DO - 10.1021/jm701623q

M3 - Article

C2 - 18578473

AN - SCOPUS:47749084644

VL - 51

SP - 4321

EP - 4330

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 14

ER -