Correction to From 6-Aminoquinolone Antibacterials to 6-Amino-7-thiopyranopyridinylquinolone Ethyl Esters as Inhibitors of <i>Staphylococcus aureus</i> Multidrug Efflux Pumps

Pieroni, Marco; Dimovska, Mirjana; Brincat, Jean Pierre; Sabatini, Stefano; Carosati, Emanuele; Massari, Serena; Kaatz, Glenn W.; Fravolini, Arnaldo

doi:10.1021/jm2000079

Cited by 6 publications

(13 citation statements)

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“…The threshold for NorA inhibition was set at 70%, while molecules with a percentage inhibition <50% were considered to be noninhibitors, as in previous publications. 16,17,21 At least three compounds which were measured to be NorA inhibitors do not inhibit Pgp. Six other compounds tested showed similar results but cannot be directly compared to compound 6, since they were tested at lower concentration due to solubility problems.…”

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confidence: 99%

“…Our group has been involved in both NorA , and Pgp in silico modeling. The entire set of compounds in the NorA data set have been projected into the Pgp in silico model, and a number of compounds for which NorA inhibitory activity is already available have been selected and tested for their activity against Pgp.…”

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confidence: 99%

“… a Structures for compounds 1 – 35 , IUPAC names for compounds 15 – 35 , and SMILES are given as Supporting Information. b Reserpine was used as a positive control for EtBr efflux inhibition. c From ref . d Tested at 10 –5 M concentration. e Tested at 10 –4 M concentration. f From ref . g Cyclosporine A was used as a positive control for R123 efflux inhibition. h Alprenolol was used as a negative control for R123 efflux inhibition. i From ref . j From ref . k From ref . …”

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confidence: 99%

“…This value was 21.1%. The threshold for NorA inhibition was set at 70%, while molecules with a percentage inhibition <50% were considered to be noninhibitors, as in previous publications. ,, …”

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confidence: 99%

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Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA

Brincat

Broccatelli

Sabatini

et al. 2012

ACS Med. Chem. Lett.

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Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA

Brincat

Broccatelli

Sabatini

et al. 2012

ACS Med. Chem. Lett.

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“…A library of seven quinolines, 61a−c, 61j, 61t, 61w, and 61y, together with other known EPIs such as 3-phenyl-1,4benzothiazines, 94 6-amino-7-thiopyranopyridinyl quinolone esters, 89 2-(4′-propoxyphenyl)quinolines, 92 pyrazolo[4,3-c]-[1,2]benzothiazines 5,5 dioxide, 95 and 5,6,7,8-tetrahydroquinolines 96 was used to develop the pharmacophore model. Sixtyfive compounds were chosen in order to obtain high homogeneity in the biological data; in particular, derivatives with a well-defined chirality for which NorA inhibitory activity was evaluated at the screening concentration of 50 μM on the NorA overexpressing S. aureus strain SA-1199B.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms

et al. 2017

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There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

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Evolution from a Natural Flavones Nucleus to Obtain 2-(4-Propoxyphenyl)quinoline Derivatives As Potent Inhibitors of the S. aureus NorA Efflux Pump

et al. 2011

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Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of substrate antimicrobial agents. Inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant phenotype. In this work, a series of 2-phenyl-4(1H)-quinolone and 2-phenyl-4-hydroxyquinoline derivatives, obtained by modifying the flavone nucleus of known efflux pump inhibitors (EPIs), were synthesized in an effort to identify more potent S. aureus NorA EPIs. The 2-phenyl-4-hydroxyquinoline derivatives 28f and 29f display potent EPI activity against SA-1199B, a strain that overexpresses norA, in an ethidium bromide efflux inhibition assay. The same compounds, in combination with ciprofloxacin, were able to completely restore its antibacterial activity against both S. aureus SA-K2378 and SA-1199B, norA-overexpressing strains.

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Correction to From 6-Aminoquinolone Antibacterials to 6-Amino-7-thiopyranopyridinylquinolone Ethyl Esters as Inhibitors of Staphylococcus aureus Multidrug Efflux Pumps

Cited by 6 publications

References 0 publications

Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA

Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA

Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms

Evolution from a Natural Flavones Nucleus to Obtain 2-(4-Propoxyphenyl)quinoline Derivatives As Potent Inhibitors of the S. aureus NorA Efflux Pump

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