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

Tomaras AP,Crandon JL,McPherson CJ,Banevicius MA,Finegan SM,Irvine RL,Brown MF,O'Donnell JP,Nicolau DP

doi

10.1128/AAC.00629-13

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

4197-207

issue

9

eissn

0066-4804

issn

1098-6596

pii

AAC.00629-13

journal_volume

57

pub_type

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