Adaptation-Based Resistance to Siderophore-Conjugated Antibacterial Agents by Pseudomonas aeruginosa

Abstract

ABSTRACTMultidrug 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 standardin vitroMIC 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 excellentin vitroactivity againstPseudomonas aeruginosawhen tested using standard assay conditions. Unfortunately, thein vitrofindings did not correlate with thein vivoresults 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 newin vitroassays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of someP. aeruginosaisolatesin vivo.