title: Synergistic interaction between proton pump inhibitors and resistance modifiers: promoting effects of antibiotics and plasmid curing.
abstract: A proton pump-deleted mutant E. coli, AG100 A, had greater sensitivity to ampicillin, tetracycline and erythromycin than the wild-type parent E. coli AG100 containing the proton pump. This antibiotic sensitivity was further increased by resistance modifiers such as the Ca2+ channel blocker (+/-) verapamil (VP) and the calmodulin antagonist promethazine (PMZ). Whereas the newly-synthesized trifluoromethyl-ketone (TF) enhanced the activity of these antibiotics against the wild-type strain, it did not enhance the activity of ampicillin against the proton pump-deleted mutant. These results suggested that TF14 had an inhibitory effect on the proton pump. Elimination of plasmids from another strain of E. coli, K12, was promoted by PMZ and 9-amino-acridine (9-AA), but not by TF14 alone. However, combinations of TF14 with either PMZ or 9-AA enhanced the plasmid elimination capacity of the latter compounds. The combination of TF14, PMZ and VP proved that the Ca2+ channel blocker was not effective by itself These results collectively suggest that TF14 inhibited the proton pump of E. coli and that it was this pump which, when inhibited by TF14, allowed more PMZ to reach its plasmid elimination target.
authors.affiliation: Department of Medical Microbiology, University of Szeged, 6720 Szeged, Dóm tér 10, Hungary.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wolfart
authors.forename: Gabriella
authors.initials: G
authors.lastname: Spengler
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
mesh_terms: D000585:Aminacrine / Q000494:pharmacology; D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004357:Drug Synergism; D004917:Erythromycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D010957:Plasmids / Q000187:drug effects*; D011398:Promethazine / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D013752:Tetracycline / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D054328:Proton Pump Inhibitors; D004917:Erythromycin; D000585:Aminacrine; D000667:Ampicillin; D014700:Verapamil; D013752:Tetracycline; D011398:Promethazine