title: Inhibition of antibiotic efflux in bacteria by the novel multidrug resistance inhibitors biricodar (VX-710) and timcodar (VX-853).
abstract: Inhibitors of mammalian multidrug efflux, such as the plant alkaloid reserpine, are also active in potentiating antibiotic activity by inhibiting bacterial efflux. Based on this precedent, two novel mammalian multiple drug resistance inhibitors, biricodar (VX-710) and timcodar (VX-853), were evaluated for activity in a variety of bacteria. Both VX-710 and VX-853 potentiated the activity of ethidium bromide (EtBr), a model efflux substrate, against three clinically significant gram-positive pathogens: Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Similar to reserpine, VX-710 and VX-853 directly blocked EtBr efflux in S. aureus. Furthermore, these compounds were effective in lowering the MICs of several clinically used antibiotics, including fluoroquinolones, suggesting that VX-710 and VX-853 are representatives of a new class of bacterial efflux inhibitors with the potential for use in combination therapy.
authors.affiliation: Vertex Pharmaceuticals, 130 Waverly St., Cambridge, MA 02139, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Mullin
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D024841:Fluoroquinolones / Q000494:pharmacology; D019450:Genes, MDR / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D010880:Piperidines; D011725:Pyridines; C106077:biricodar; C494139:timcodar