title: Adaptation-based resistance to siderophore-conjugated antibacterial agents by Pseudomonas aeruginosa.
abstract: Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo.
authors.affiliation: Antibacterials Research Unita and Medicinal Chemistry, Groton, Connecticut, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Tomaras
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McPherson
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Banevicius
authors.forename: Steven M
authors.initials: SM
authors.lastname: Finegan
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Irvine
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: John P
authors.initials: JP
authors.lastname: O'Donnell
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D005260:Female; D007501:Iron / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000737:chemistry / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D017262:Siderophores / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; C000603335:MB-1 monobactam compound; D008997:Monobactams; D009842:Oligopeptides; D011728:Pyridones; D017262:Siderophores; C042453:pyoverdin; D007501:Iron