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<jats:title>ABSTRACT</jats:title> <jats:p> The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against <jats:named-content content-type="genus-species">Pseudomonas aeruginosa</jats:named-content> and <jats:named-content content-type="genus-species">Acinetobacter baumannii</jats:named-content> . Here, we investigated the mechanism of action of these molecules in <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> . We identified two novel TonB-dependent receptors, termed <jats:italic>Ab</jats:italic> -PiuA and <jats:italic>Ab</jats:italic> -PirA, that are required for the antimicrobial activity of both agents. Deletion of either <jats:italic>piuA</jats:italic> or <jats:italic>pirA</jats:italic> in <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host <jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content> increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> and their orthologues from <jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content> were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> , forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens. </jats:p>

Original publication

DOI

10.1128/aac.02531-16

Type

Journal article

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

04/2017

Volume

61