title: Potentiation of antibacterial activity of the MB-1 siderophore-monobactam conjugate using an efflux pump inhibitor.
abstract: Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability.
authors.affiliation: Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA andrew.tomaras@pfizer.com.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Tomaras
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McPherson
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology*; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D011728:Pyridones / Q000494:pharmacology*; D012110:Reserpine / Q000494:pharmacology; D017262:Siderophores / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; C000603335:MB-1 monobactam compound; D008997:Monobactams; D011728:Pyridones; D017262:Siderophores; D012110:Reserpine