title: Synthesis and evaluation of fluoroquinolone derivatives as substrate-based inhibitors of bacterial efflux pumps.
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.
authors: Division of Medicinal and Natural Products Chemistry, University of Iowa, College of Pharmacy, 115 S. Grand Avenue, Iowa City, IA 52242, USA.
authors: Nadezhda
authors: N
authors: German
authors: Peng
authors: P
authors: Wei
authors: Glenn W
authors: GW
authors: Kaatz
authors: Robert J
authors: RJ
authors: Kerns
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; D024841:Fluoroquinolones