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

• DOI: 10.1128/aac.00629-13
• Publication Date: 2013-06-18T03:04:57Z
• Authors: Andrew P. Tomaras; Jared L. Crandon; Craig J. McPherson; Mary Anne Banevicius; Steven M. Finegan; Rebecca L. Irvine; Matthew F. Brown; John P. O'Donnell; David P. Nicolau
• Keywords: Gram-Negative Bacteria

ABSTRACT Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, received significant attention recent years. While standard vitro MIC and frequency methods demonstrate compounds potent, broad-spectrum agents whose activity should not be threatened unacceptably high spontaneous rates, recapitulation results animal models can prove unreliable, partially because differences availability different methods. Here, we describe characterization MB-1, a novel siderophore-conjugated monobactam demonstrates excellent against Pseudomonas aeruginosa when tested using assay conditions. Unfortunately, findings did correlate with vivo obtained, as multiple strains were effectively treated MB-1 despite having low MICs. To address this, also development assays predictive efficacy mouse models, provide evidence competition native siderophores could contribute recalcitrance some P. isolates .