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Synthesis and evaluation of fluoroquinolone derivatives as substrate-based inhibitors of bacterial efflux pumps.

European journal of medicinal chemistry (2008-03-25)
Nadezhda German, Peng Wei, Glenn W Kaatz, Robert J Kerns
ABSTRACT

Bacterial efflux pump systems contribute to antimicrobial resistance in pathogenic bacteria. The co-administration of bacterial efflux pump inhibitors with antibiotics is being pursued to overcome efflux-mediated resistance to antibiotics. In this study we investigated a strategy for converting broad-spectrum efflux pump substrates, fluoroquinolone antibacterial agents which are inherently recognized by most efflux transporters, into expanded spectrum efflux pump inhibitors. Employing this strategy against organisms expressing efflux pumps from the MFS, MATE and RND classes of pump systems, we report here the identification of an ofloxacin-based EPI that is a potent inhibitor of MFS (NorA) and MATE (MepA) efflux pumps in Staphylococcus aureus. The methods described here outline a process that we feel will be broadly applicable to the systematic identification of bacterial efflux pump inhibitors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ciprofloxacin, ≥98% (HPLC)
Sigma-Aldrich
Ofloxacin, fluoroquinolone antibiotic
Sigma-Aldrich
Reserpine
Sigma-Aldrich
1,3-Diphenylurea, 98%
Supelco
Reserpine Standard for LC-MS, analytical standard, for LC-MS
Supelco
Ofloxacin, VETRANAL®, analytical standard

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